You are on page 1of 824

Academic Press is an imprint of Elsevier

525 B Street, Suite 1900, San Diego, CA 92101-4495, USA


30 Corporate Drive, Suite 400, Burlington, MA 01803, USA
32 Jamestown Road, London, NW1 7BY, UK
Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands

Second edition 2009

Copyright 2009 Elsevier Ltd. All rights reserved.

No part of this publication may be reproduced, stored in a retrieval system


or transmitted in any form or by any means electronic, mechanical, photocopying,
recording or otherwise without the prior written permission of the publisher

Permissions may be sought directly from Elseviers Science & Technology Rights
Department in Oxford, UK: phone (44) (0) 1865 843830; fax (44) (0) 1865 853333;
email: permissions@elsevier.com. Alternatively you can submit your request
online by visiting the Elsevier web site at http://elsevier.com/locate/permissions,
and selecting obtaining permission to use Elsevier material

Notice

No responsibility is assumed by the publisher for any injury and/or damage to persons
or property as a matter of products liability, negligence or otherwise, or from any use
or operation of any methods, products, instructions or ideas contained in the material
herein. Because of rapid advances in the medical sciences, in particular, independent
verication of diagnoses and drug dosages should be made

Medicine is an ever-changing eld. Standard safety precautions must be followed, but as


new research and clinical experience broaden our knowledge, changes in treatment and
drug therapy may become necessary or appropriate. Readers are advised to check the most
current product information provided by the manufacturer of each drug to be administered
to verify the recommended dose, the method and duration of administrations, and
contraindications. It is the responsibility of the treating physician, relying on experience
and knowledge of the patient, to determine dosages and the best treatment for each
individual patient. Neither the publisher nor the authors assume any liability for any
injury and/or damage to persons or property arising from this publication

British Library Cataloguing-in-Publication Data


A catalogue record for this book is available from the British Library

Library of Congress Cataloging-in-Publication Data


A catalog record for this book is available from the Library of Congress

ISBN: 978-0-12-374001-4

For information on all Academic Press publications


visit our website at elsevierdirect.com

Printed and bound in USA

09 10 11 12 10 9 8 7 6 5 4 3 2 1
Preface to the 2nd Edition

In the 6 years since the publication of the rst edition of Asthma and COPD there has been
substantial progress in understanding the biological basis of both of these obstructive diseases. In
contrast both our understanding of the physiological basis of these conditions and their treatment
has improved very little. We rmly believe that the progress made in understanding the basic disease
biology that has accrued since 2002 will lead, in the years to come to new and better treatments of
these crippling obstructive airway diseases. As our knowledge advances, we now appreciate the areas
of overlap and distinction between these two conditions which share many physiological similari-
ties. Most of the chapters of this book highlight both the similarities and dierences between these
conditions.
In this era of widely available information on the internet it is reasonable to ask what value is
served by a book of this type? The answer is simple. The editors have assembled the worlds experts
on these topics and commissioned them to write succinct reviews focusing on their particular area
of expertise. For the student of the biology or treatment of these conditions, this compilation is an
important resource of up-to-date information. For the researcher or clinician, the investigative or
clinical problems that each of face on a daily basis are clearly illuminated by topic experts. We hope
that you will nd this summary of value to you in understanding these two highly variegated, closely
similar but clearly distinct entities at the biological and clinical level.

Peter J. Barnes
Jeery M. Drazen
Stephen I. Rennard
Neil C. Thomson

ix
About the Editors

Peter J Barnes, DM, DSc, FRCP, FMedSci, the Scientic Committee of the British Lung
FRS, is a Professor of Thoracic Medicine at Foundation. He has co-edited several textbooks
the National Heart and Lung Institute, Head on asthma and COPD and published over 150
of Respiratory Medicine at Imperial College, peer-reviewed papers on asthma. His current
and Honorary Consultant Physician at Royal research interests include corticosteroid insen-
Brompton Hospital, London. He qualied at sitivity in smokers with asthma, biomarkers in
Cambridge and Oxford Universities and was asthma and COPD and assessment of novel
appointed to his present post in 1987. He has treatments for asthma.
published over 1000 peer-review papers on
asthma, COPD, and related topics and has Jerey M Drazen, MD, was born in St. Louis,
edited over 40 books. He is also amongst the Missouri. He graduated from Tufts University
top 50 most highly cited researchers in the with a major in Physics, and from Harvard
world and has been the most highly cited clini- Medical School. He served his medical intern-
cal scientist in the United Kingdom and the ship and residency at Peter Bent Brigham
most highly cited respiratory researcher in the Hospital in Boston and was a Clinical Fellow
world over the last 20 years. He was elected a and Research Fellow at Harvard Medical
Fellow of the Royal Society in 2007, the rst School and Harvard School of Public Health.
respiratory researcher for over 150 years. He is Thereafter, he joined the Pulmonary Divisions
currently a Member of the Scientic Committee of the Harvard hospitals and served for many
of the WHO/NIH global guidelines on asthma years as Chief of the Combined Pulmonary
(GINA) and COPD (GOLD). He also serves Divisions at Beth Israel and Brigham and
on the Editorial Board of over 30 journals and Womens Hospitals.
is currently an Associate Editor of Chest and Currently, he is a Senior Physician at
Respiratory Editor of PLoS Medicine. He has the Brigham and Womens Hospital, and the
given several prestigious lectures, including the Distinguished Parker B. Francis Professor of
Amberson Lecture at the American Thoracic Medicine at Harvard Medical School, as well
Society and the Sadoul Lecture at the European as Professor of Physiology, Harvard School of
Respiratory Society. Public Health, and adjunct Professor of Medicine
at Boston University School of Medicine.
Neil C Thomson, MD, FRCP, is a Professor He has served on the NIH Respiratory
of Respiratory Medicine at the University and Applied Physiology Study Section, the
of Glasgow, Head of Respiratory Medicine NIH Pulmonary Disease Advisory Council,
within the Division of Immunology, Infection the NIH Lung Biology and Pathology Study
& Inammation, and Honorary Consultant Section, and the NHLBI Advisory Council.
at Gartnavel General Hospital, Glasgow. He Through his research, he dened the role
graduated from the University of Glasgow and of novel endogenous chemical agents in asthma.
undertook postgraduate training in Glasgow, This led to four new licensed pharmaceuticals
London and McMaster University, Canada. for asthma used in the treatment of millions of
He is a former Member of the Committee people worldwide. He has published nearly 500
for Safety of Medicine and former Chair of papers and edited 6 books.

xi
About the Editors

He has been a member of the Editorial Boards of many Institutes of Health where he remained for seven years,
prestigious journals, including the Journal of Applied Physiology, conducting research in the cell biology of lung disease.
American Journal of Physiology, Pulmonary Pharmacology, He joined the University of Nebraska in 1984 as Chief
Experimental Lung Research, Journal of Clinical Investigation, of Pulmonary and Critical Care, a position he retained
American Journal of Respiratory Cell and Molecular Biology, and until 1997. He was the Director of the Nebraska Oce of
the American Journal of Medicine. In addition, he has been an Tobacco Control and Research from 1997 until 2008.
associate editor of the Journal of Clinical Investigation and the Dr. Rennard currently serves on the Board of
American Review of Respiratory Disease. Directors of the COPD Foundation and the Alpha-1
In 2000, he assumed the post of Editor-in-Chief of Foundation. He is a member of the American Thoracic
the New England Journal of Medicine. During his tenure, Society Committee on Corporate Relations and the
the journal has published major papers advancing the sci- National Heart Lung Education Program Executive
ence of medicine, including the rst descriptions of SARS Committee. He is an external advisor to the Thomas Petty
and papers modifying the treatment of cancer, heart disease, Aspen Lung Conference and the University of California-
and lung disease. The journal, which has more than half a Davis Pulmonary Training Grant.
million readers every week, has the highest impact factor of Dr. Rennard is active in several professional societies
any medical journal publishing original research. and has previously served on the Board of Directors for the
American Thoracic Society, the Council of the American
Stephen I Rennard, MD, is Larson Professor of Medicine Lung Association and was a Governor for the American
in the Pulmonary and Critical Care Medicine Section of College of Chest Physicians. He served on the American
the Department of Internal Medicine at the University Board of Internal Medicine, Pulmonary Section and was a
of Nebraska Medical Center in Omaha, Nebraska, and member of the expert panel which prepared the global GOLD
courtesy Professor of the Department of Pathology and guidelines for COPD for the WHO/NHLBI. He has served
Microbiology and the Department of Genetics, Cell on several task force committees, including the ATS/ERS task
Biology and Anatomy. He received an AB with honors in force that prepared the ATS/ERS joint COPD Standards.
Folklore and Mythology from Harvard University and an Professor Rennard maintains an active program of
MD with honors from the Baylor College of Medicine, clinical investigation in COPD and smoking cessation and
Houston, Texas. He completed internal medicine train- a program of basic research in the mechanisms of lung tis-
ing at Barnes Hospital, Washington University, St. Louis, sue repair and remodeling, including the role of stem cells
Missouri and trained in Pulmonary Diseases at the National in disease pathogenesis and repair.

xii
List of Contributors

Ian M. Adcock (31) Joan Albert Barber (20)


National Heart and Lung Institute, Imperial Servei de Pneumologia, Hospital Clinic,
College School of Medicine, London, UK IDIBAPS, Universitat de Barcelona, Barcelona,
Spain
Alvar Agusti (44)
Hospital University Son Dureta, Servi Peter J. Barnes (32, 33, 34, 40, 49, 50, 51, 52, 61)
Pneumologia, Palma de Majorca, Spain National Heart and Lung Institute (NHLI),
Fundacion Caubet-CIMERA Clinical Studies Unit, Imperial College,
CIBER Enfermedades Respiratorias London, UK

Jennifer A. Alison (38) Bianca Begh (41)


Discipline of Physiotherapy, Faculty of Health Department of Respiratory Diseases,
Sciences, University of Sydney, Lidcombe, University of Modena and Reggio Emilia,
NSW, Australia Modena, Italy

Yassine Amrani (18)


Richard C. Boucher (16)
Department of Infection, Immunity and
Department of Medicine, The University of
Inammation, University of Leicester, UK
North Carolina at Chapel Hill, Chapel Hill,
NC, USA
Sandra D. Anderson (38)
Department of Respiratory Medicine,
Royal Prince Alfred Hospital, Camperdown, Andrew Briggs (62)
NSW, Australia Section of Public Health and Health Policy,
University of Glasgow, Glasgow, Scotland, UK
Kjetil Ask (29)
Centre for Gene Therapeutics, Department of Guy G. Brusselle (10)
Pathology and Molecular Medicine, McMaster Department of Pulmonary Medicine, Erasmus
University, Hamilton, ON, Canada University Medical Center, Rotterdam,
The Netherlands
Jon Ayres (39)
Department of Environmental and A. Sonia Buist (1)
Occupational Medicine, Liberty Safe Work Division of Pulmonary and Critical Care
Research Centre, University of Aberdeen, Medicine, Oregon Health Sciences
Aberdeen, UK University, Portland, OR, USA

xiii
List of Contributors

Kimberlie Burns (16) Christopher J. Corrigan (55)


Department of Medicine, The University of North Carolina Department of Asthma, Allergy and Respiratory Science,
at Chapel Hill, Chapel Hill, NC, USA Guys Hospital, London, UK
MRC and Asthma UK Centre in Allergic Mechanisms of
Andrew Bush (65) Asthma Kings College London, UK
Department of Respiratory Pediatrics, Imperial
College of Science, Technology and Manuel G. Cosio (13)
Medicine, Royal Brompton Hospital and Meakins-Christie Laboratories and the Respiratory
National Heart and Lung Institute, London, UK Division, Department of Medicine, McGill University,
Montreal, Quebec, Canada
Carlos A. Camargo Jr. (64)
Department of Emergency Medicine, Massachusetts Harvey O. Coxson (43)
General Hospital, Harvard Medical School, Boston, MA, Department of Radiology, James Hogg iCAPTURE Centre
USA for Cardiovascular and Pulmonary Research, University of
British Columbia, Vancouver, BC, Canada
Gaetano Caramori (31)
Adnan Custovic (46)
National Heart and Lung Institute, Imperial College
University of Manchester, Manchester, UK
School of Medicine, London, UK
Marc Decramer (58)
George H. Caughey (9) Respiratory Rehabilitation and Respiratory Division,
Cardiovascular Research Institute and Department of University Hospital, Leuven, Belgium
Medicine, University of California at San Francisco, USA
Faculty of Kinesiology and Rehabilitation Sciences,
Bartolome R. Celli (54) Department of Rehabilitation Sciences, Katholieke
Division of Pulmonary and Critical care, Universiteit Leuven, Leuven, Belgium
Caritas -St. Elizabeths Medical Center, Tufts University,
Dawn L. DeMeo (2)
Boston, MA, USA
Channing Laboratory, Brigham and Womens Hospital,
Harvard Medical School, Boston, MA, USA
Michael A. Chandler (47)
University of Nebraska Medical Center, Omaha, NE, USA Jerey M. Drazen (24, 33)
Department of Medicine, Pulmonary Division,
Richard N. Channick (56)
Birgham and Womens Hospital, Boston, MA, USA
Division of Pulmonary and Critical Care Medicine,
University of California, San Diego School of Medicine, Harvard Medical School, Editorial Oce New England
La Jolla, CA, USA Journal of Medicine, Boston, MA, USA

Leonardo M. Fabbri (41)


Moira Chan-Yeung (36)
Department of Respiratory Diseases, University of Modena
Department of Medicine, Respiratory Division, University
and Reggio Emilia, Modena, Italy
of British Columbia, Vancouver, BC, Canada
Jack Gauldie (29)
Kian Fan Chung (27, 52) Centre for Gene Therapeutics, Department of Pathology
National Heart and Lung Institute (NHLI), and Molecular Medicine, McMaster University, Hamilton,
Imperial College, London, UK ON, Canada

Donald W. Cockcroft (35) Maurice Godfrey (22)


Division of Respirology, Critical Care and Sleep Medicine, Center for Human Molecular Genetics, Munroe Meyer
Department of Medicine, University of Sasketchewan, Institute, University of Nebraska Medical Center, Omaha,
Royal University Hospital, Saskatoon, Saskatchewan, NE, USA
Canada
Stefano Guerra (3)
Lorenzo Corbetta (41) Arizona Respiratory Center and Mel and Enid Zuckerman
Department of Respiratory Diseases, University of Firenze, College of Public Health, University of Arizona,Tucson,
Firenze, Italy AZ, USA

xiv
List of Contributors

Ian P. Hall (48) Onn Min Kon (49)


Division of Therapeutics and Molecular Medicine, National Heart and Lung Institute (NHLI), Clinical
University Hospital of Nottingham, Nottingham, UK Studies Unit, Imperial College, London, UK

Trevor T. Hansel (49) Samuel L. Krachman (57)


National Heart and Lung Institute (NHLI), Clinical Section of Pulmonary and Critical Care Medicine,
Studies Unit, Imperial College, London, UK Temple University School of Medicine, Philadelphia,
PA, USA
James C. Hogg (6)
UBC McDonald Research Laboratories, St. Pauls Hospital, Vera P. Krymskaya (18)
University of British Columbia, Vancouver, BC, Canada Pulmonary, Allergy and Critical Care Division, Airways
Biology Initiative, University of Pennsylvania,
Stephen T. Holgate (7) Philadelphia, PA, USA
School of Medicine, University of Southampton,
Southampton, UK Bart N. Lambrecht (10)
Department of Respiratory Medicine, University Hospital
Gabor Horvath (19) Ghent, Belgium
Department of Pulmonology, Semmelweiss University, Department of Pulmonary Medicine, Erasmus University,
Budapest, Hungary Rotterdam, The Netherlands

Charles G. Irvin (5) Georey J. Laurent (15)


Department of Medicine and Physiology, University of UCLMS, Center for Respiratory Research, University
Vermont College of Medicine, Burlington, VT, USA St/Rayne Institute, London, UK

Kazuhiro Ito (30) Bruce D. Levy (24)


Section of Airway Disease, National Heart and Lung Department of Medicine, Pulmonary Division,
Institute, Imperial College, London, UK Brigham and Womens Hospital, Boston, MA, USA

Fabrizio Luppi (41)


Wim Janssens (58)
Department of Respiratory Diseases, University of
Respiratory Rehabilitation and Respiratory Division,
Modena and Reggio Emilia, Modena, Italy
University Hospital, Leuven, Belgium
Jean-Luc Malo (36)
Sebastian L. Johnston (37) Department of Chest Medicine, Sacr-Coeur Hospital,
Department of Respiratory Medicine, National Heart and Montreal, Canada
Lung Institute, Imperial College London, London, UK
James G. Martin (13)
Susan Kennedy (36) Meakins-Christie Laboratories and the Respiratory
School of Environmental Health, University of British Division, Department of Medicine, McGill University,
Columbia, Vancouver, BC, Canada Montreal, Quebec, Canada

Sergei A. Kharitonov (30, 42) Fernando D. Martinez (3)


Section of Airway Disease, National Heart and Lung Arizona Respiratory Center and Mel and Enid Zuckerman
Institute, Imperial College, London, UK College of Public Health, University of Arizona, Tucson,
AZ, USA
Darryl A. Knight (15)
Department of Pharmacology and Therapeutics, Simon D. Message (37)
University of British Columbia, Vancouver, BC, Canada Department of Respiratory Medicine, National Heart and
Lung Institute, Imperial College London, London, UK
Martin Kolb (29)
Centre for Gene Therapeutics, Department of Pathology Lynne A. Murray (15)
and Molecular Medicine, McMaster University, Manager of Pharmocology Promedior, Inc.
Hamilton, ON, Canada Malvern, PA, USA

xv
List of Contributors

Paul M. OByrne (23) Stephen I. Rennard (34, 47, 66)


Firestone Institute for Respiratory Health, St. Josephs Pulmonary and Critical Care Medicine, University of
Healthcare and Department of Medicine, McMaster Nebraska Medical Center, Omaha, NE, USA
University, Hamilton, ON, Canada
Roberto Rodrguez-Roisin (20)
Reynold A. Panettieri Jr. (18) Servei de Pneumologia, Hospital Clinic, IDIBAPS,
Pulmonary, Allergy and Critical Care Division, Airways Universitat de Barcelona, Barcelona, Spain
Biology Initiative, University of Pennsylvania, Philadelphia,
PA, USA Duncan F. Rogers (17)
Section of Airway Disease, National Heart and Lung
Martyn R. Partridge (68) Institute, Imperial College, London, UK
The Faculty of Medicine, Imperial College, London, UK
Brian H. Rowe (64)
Rodolfo M. Pascual (63)
Department of Emergency Medicine, University of
Section on Pulmonary, Critical Care, Allergy and
Alberta, and Capital Health, Edmonton, AB, Canada
Immunologic Diseases, Department of Internal Medicine,
Wake Forest University School of Medicine, Medical
Lewis J. Rubin (56)
Center Boulevard, Winston-Salem, NC, USA
Division of Pulmonary and Critical Care Medicine,
University of California, San Diego School of Medicine,
Ian D. Pavord (42)
La Jolla, CA, USA
Department of Respiratory Medicine and Thoracic Surgery,
Institute for Lung Health, Gleneld Hospital,
Elizabeth Sapey (14)
Leicester, UK
Department of Medicine, Birmingham University,
Birmingham, UK
James E. Pease (26)
Leukocyte Biology Section, National Heart and
Sanjay Sethi (53)
Lung Institute, Imperial College London, London, UK
Division of Pulmonary, Critical Care and Sleep Medicine,
Department of Medicine, University of Bualo, State
Stephen P. Peters (63)
University of New York, and Veterans Aairs Western
Section on Pulmonary, Critical Care, Allergy and
New York Health Care System, Bualo, New York, USA
Immunologic Diseases, Department of Internal Medicine,
Wake Forest University School of Medicine, Medical
Center Boulevard, Winston-Salem, NC, USA Pallav L. Shah (59)
Royal Brompton Hospital and National Heart and
Michael I. Polkey (59) Lung Institute, London, UK
Royal Brompton Hospital and National Heart and
Lung Institute, London, UK Steven D. Shapiro (8, 28)
Department of Medicine, University of Pittsburgh,
Dirkje S. Postma (4) Pittsburgh, PA, USA
Department of Pulmonology, University Medical Center
Groningen, University of Groningen, Groningen, The Dean Sheppard (21)
Netherlands Department of Medicine and Lung Biology Center,
University of California, San Francisco, CA, USA
Irfan Rahman (25)
Department of Environmental Medicine, Lung Biology Stephanie A. Shore (8)
and Disease Program, University of Rochester Medical Molecular and Integrative Physiological Sciences Program,
Center, Rochester, NY, USA Harvard School of Public Health, Boston, MA, USA

Scott H. Randell (16) Edwin K. Silverman (4)


Departments of Cell and Molecular Physiology and Channing Laboratory and Division of Pulmonary and
Medicine, The University of North Carolina at Chapel Hill, Critical Care Medicine, Brigham and Womens Hospital,
NC, USA Harvard Medical School, Boston, MA, USA

xvi
List of Contributors

Dagmar Simon (12) Galen B. Toews (11)


Department of Dermatology, Inselspital, University of Division of Pulmonary and Critical Care Medicine,
Bern, Bern, Switzerland University of Michigan Health System, Ann Arbor,
MI, USA
Hans-Uwe Simon (12)
Department of Pharmacology, University of Bern, Bern,
Thierry Troosters (58)
Switzerland
Respiratory Rehabilitation and Respiratory Division,
University Hospital, Leuven, Belgium
Michael W. Sims (18)
Pulmonary, Allergy and Critical Care Division, Airways Faculty of Kinesiology and Rehabilitation Sciences,
Biology Initiative, University of Pennsylvania, Philadelphia, Department of Rehabilitation Sciences, Katholieke
PA, USA Universiteit Leuven, Leuven, Belgium

Don D. Sin (45) Adam Wanner (19)


The James Hogg iCAPTURE Center for Cardiovascular Division of Pulmonary and Critical Care Medicine,
and Pulmonary Research, St. Pauls Hospital, Vancouver, University of Miami Miller School of Medicine, Miami,
BC, Canada FL, USA

Helen Starkie (62)


Section of Public Health and Health Policy, University of Jadwiga A. Wedzicha (67)
Glasgow, Glasgow, Scotland, UK Department of Respiratory Medicine, University College
of London, London, UK
Robert A. Stockley (14)
Lung Investigation Unit, University Hospital Birmingham, Scott T. Weiss (2)
NHS Foundation Trust, Edgbaston, Birmingham, UK Channing Laboratory, Brigham and Womens Hospital,
Harvard Medical School, Boston, MA, USA
Andrew J. Tan (49)
National Heart and Lung Institute (NHLI), Clinical
Studies Unit, Imperial College, London, UK Timothy J. Williams (26)
Leukocyte Biology Section, National Heart and Lung
Neil C. Thomson (32, 40, 60) Institute, Imperial College London, London, UK
Department of Respiratory Medicine, Division of
Immunology, Infection and Inammation, University of Ashley Woodcock (46)
Glasgow, Glasgow, UK, University of Manchester, Manchester, UK

Omar Tliba (18)


Olivia Wu (62)
Pulmonary, Allergy and Critical Care Division, Airways
Section of Public Health and Health Policy,
Biology Initiative, University of Pennsylvania,
University of Glasgow, Glasgow, Scotland, UK
Philadelphia, PA, USA

Martin J. Tobin (57) Zhou Xing (29)


Loyola University of Chicago, Stritch School of Medicine Centre for Gene Therapeutics, Department of Pathology
and Hines Veterans Administration Hospital, Maywood, and Molecular Medicine, McMaster University, Hamilton,
IL, USA ON, Canada

xvii
Definitions,
1
PART

Epidemiology, and
Genetics of Asthma
and COPD
Definitions
1
CHAPTER

Denitions of diseases evolve over time as our of the GINA Guidelines [1] proposes an oper-
understanding of them changes. For example, ational description of asthma as:
A. Sonia Buist
until recently, the presence or absence of revers- Division of Pulmonary and Critical Care
ibility was considered to be the key distinction a chronic inammatory disorder of the air- Medicine, Oregon Health and Sciences
between asthma and chronic obstructive pul- ways in which many cells and cellular ele-
University, Portland, OR, USA
monary disease (COPD) with reversible air- ments play a role. The chronic inammation
ow obstruction the hallmark of asthma, and is associated with airway hyperresponsiveness
irreversible airow obstruction the hallmark of that leads to recurrent episodes of wheezing,
COPD. Better understanding of both diseases breathlessness, chest tightness, and coughing,
has brought new denitions that acknowl- particularly at night or in the early morn-
edge the overlap and highlight the similarities ing. These episodes are usually associated with
and dierences between them. The important widespread, but variable, airow obstruction
change in our understanding is the recognition within the lung that is often reversible either
that chronic inammation underlies both dis- spontaneously or with treatment.
eases. The nature of the inammation diers,
however, as does the response to anti-inam- This is very similar to the denition pro-
matory medications, as described in detail in posed by the National Asthma Education and
later chapters. This chapter draws heavily on the Prevention Program in their 1997 guidelines [3].
latest information on asthma and COPD that Both denitions imply that asthma is one disor-
is included in the guidelines on the diagnosis der, rather than multiple complex disorders and
and management of these diseases from two syndromes a notion that is receiving increasing
widely respected global initiatives, the Global attention [4, 5].
Initiative for Asthma (GINA) [1] and the
Global Initiative for Chronic Obstructive Lung
Disease (GOLD) [2], as updated in 2006. COPD
Until quite recently, denitions of COPD used
to include the terms chronic bronchitis and
DEFINITIONS emphysema. The GOLD Guidelines, rst
published in 2002 [6], and revised in 2006
[2], the American Thoracic Society/European
Asthma Respiratory Society (ATSERS) Guidelines
published in 2004 [7], and the NICE
Most of the denitions for asthma have empha- Guidelines [8, 9] published in 2004 deliberately
sized the characteristics of uctuations over omitted these terms and used just the umbrella
time in bronchoconstriction and the reversible term COPD. The main reason for this is that
nature of the disease [1, 3]. As the pathophysi- the use of many dierent terms for COPD has
ological basis of asthma became clearer, deni- led to confusion on the part of health-care pro-
tions began to include a statement about the viders and the public. This in turn has stood in
pathological characteristics. The 2006 revision the way of COPD becoming widely recognized.

3
Asthma and COPD: Basic Mechanisms and Clinical Management

The 2006 revision of the GOLD guidelines [2]denes COPD belonging to a spectrum of diseases that all cause
COPD as: airow obstruction, to the concept of them as very dier-
ent diseases, and most recently to them both being inam-
a preventable and treatable disease with some signicant
matory diseases with important similarities and dierences,
extrapulmonary eects that may contribute to severity in
a theme that is taken up more fully in subsequent chapters.
individual patients. Its pulmonary component is charac-
The present thinking is illustrated in Fig. 1.1 from the 2006
terized by airow limitation that is not fully reversible.
GOLD guidelines, which shows both diseases involving an
The airow limitation is usually progressive and associ-
inammatory response that causes airow limitation, but
ated with an abnormal inammatory response of the lung
through geneenvironment interactions with dierent sen-
to noxious particles of gases.
sitizing agents, cell populations, and mediators. The airow
This denition includes the phrase preventable and limitation ranges from completely reversible (the asthma end
treatable to emphasize the importance of a positive attitude of the spectrum) to completely irreversible (the COPD end
to outcome and encourage a more active approach to man- of the spectrum). It is important to emphasize that COPD
agement. This denition also stresses that extrapulmonary and asthma often coexist, so the clinical picture may reect
eects [10, 11] are an integral part of COPD and need to be both conditions which may complicate the diagnostic proc-
taken into consideration in the diagnosis and management. ess and the pathological features. For example, some patients
with COPD have features of asthma and a mixed popula-
tion of inammatory cells; some patients with longstanding
asthma develop the pathological features of COPD.
SIMILARITIES AND DIFFERENCES Although the similarities between the diseases are
striking, it is the dierences in the inammatory processes
between the two diseases that dene their natural histories,
Over the past 30 years, the thinking about asthma and clinical presentations, and approaches to management. The
COPD has swung between the concept of asthma and major dierences in the pulmonary inammation between

Asthma COPD

Allergens Cigarette smoke

Epithelial cells Mast cell Alveolar macrophage Epithelial cells

CD4 cell CD8 cell


Eosinophils Neutrophils
(Th2) (Tc1)

Bronchoconstriction and Small airway fibrosis and


airway hyperresponsiveness alveolar destruction

Not fully
Reversible Airflow limitation
reversible
FIG. 1.1 Inflammatory cascade in
COPD and asthma (adapted from
Ref. [2] with permission).

4
Definitions 1
TABLE 1.1 Differences in pulmonary inflammation in COPD and asthma.

COPD Asthma Severe asthma

Cells Neutrophils  Eosinophils  Neutrophils 


Macrophages  Macrophages  Macrophages
CD8 T-cells (Tc1) CD4 T-cells (Th2) CD4 T-cells (Th2), CD8 T-cells (Tc1)

Key mediators IL-8 Eotaxin IL-8


TNF-, IL-1, IL-6 IL-4, IL-5, IL-13 IL-5, IL-13
NO  NO  NO 

Oxidative stress   

Site of disease Peripheral airways Proximal airways Proximal airways


Lung parenchyma Peripheral airways
Pulmonary vessels

Consequences Squamous metaplasia Fragile epithelium


Mucous metaplasia Mucous metaplasia
Small airway fibrosis Basement membrane
ParenchymaI destruction Bronchoconstriction
Pulmonary vascular remodeling

Response to therapy Small b/d response Large b/d response Smaller b/d response
Poor response to steroids Good response to steroids Reduced response to steroids

Source: From Ref. [2] with permission.


Notes: NO: nitric oxide; b/d: bronchodilator.

asthma and COPD are described in Table 1.1 from the TABLE 1.2 Classification of asthma severity by clinical features before
2006 GOLD report. These dierences are further explored treatment.
in later chapters.
Intermittent
Symptoms less than once a week
Severity classification Brief exacerbations
Nocturnal symptoms not more than twice a month
Both asthma and COPD are often stratied by severity, FEV1 or PEF  80% predicted
but the reason for this stratication is dierent for the two PEF or FEV1 variability  20%
conditions. In the 2006 GINA guidelines, the emphasis has
changed from using a severity classication to guide man- Mild persistent
agement to using a classication based on asthma control to Symptoms more than once a week but less than once a day
guide management. The GINA guidelines now recommend Exacerbations may affect activity and sleep
that asthma classication based on severity should now only Nocturnal symptoms more than twice a month
be used for research purposes. Tables 1.2 and 1.3 show the FEV1 or PEF  80% predicted
GINA severity classications based on lung function and PEF or FEV1 variability  2030%
asthma control, respectively.
For COPD, a severity classication based on spirometry Moderate persistent
is recommended for educational purposes, but not for guiding
Symptoms daily
management (Table 1.4). The current recommendation is that
Exacerbations may affect activity and sleep
treatment of COPD should be driven by the need to reduce
Nocturnal symptoms more than once a week
and control symptoms, not by level of lung function.
Daily use of inhaled short-acting 2-agonist
FEV1 or PEF 6080% predicted
PEF or FEV1 variability  30%
Differentiating between asthma
and COPD Severe persistent
Symptoms daily
It would be easy to dierentiate between asthma and COPD
Frequent exacerbations
if the latter occurred only in smokers and asthma in non-
Frequent nocturnal asthma symptoms
smokers. In fact, there is a clear diagnostic bias on the part of
Limitation of physical activities
physicians, with COPD more likely to be diagnosed in men
FEV1 or PEFs 60%  predicted
and asthma in women [12]. It is important to emphasize
PEF or FEV1 variability  30%
that both conditions may coexist in an individual, so many
will have the clinical and pathophysiological features of both Source: From Ref. [1] with permission.

5
Asthma and COPD: Basic Mechanisms and Clinical Management

TABLE 1.3 Levels of asthma control.

Controlled (all of the Partly controlled (any measure


Characteristic following) present in any week) Uncontrolled

Daytime symptoms None (twice or less/week) More than twice/week

Limitations of activities None Any

Nocturnal symptoms/awakening None Any


Three or more features of partly
Meed for reliever/rescue treatment None (twice or less/week) More than twice/week controlled asthma present in any week

Lung function (PEF or FEV1)a Normal 80% predicted or personal best


(if known)

Exacerbations None One or more/yearb Once in any weekc

Source: From Ref. [1] with permission.


a
Lung function is not a reliable test for children 5 years and younger.
b
Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate.
c
By definition, an exacerbation in any week makes that an uncontrolled asthma week.

TABLE 1.4 Spirometric classification of COPD severity based on post- TABLE 1.5 Clinical features of COPD and asthma.
bronchodilator FEV1.
Diagnosis Suggestive features
Stage 1: Mild FEV1/FVC  0.70
FEV1  80% predicted COPD Onset in mid-life
Symptoms slowly progressive
Stage II: Moderate FEV1/FVC  0.70
50%  FEV1  80% predicted Long history of tobacco smoking
Dyspnea during exercise
Stage III: Severe FEV1/FVC  0.70
Largely irreversible airflow limitation
30%  FEV1  50% predicted
Asthma Onset early in life (often childhood)
Stage IV: Very severe FEV1/FVC  0.70
Symptoms vary from day to day
FEV1  30% predicted or FEV1 
50% predicted plus chronic Symptoms at night/early morning
respiratory failure Allergy, rhinitis, and/or eczema also present
Family history of asthma
Source: From Ref. [2] with permission.
Notes: FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity: respiratory Largely reversible airflow limitation
failure: arterial partial pressure of oxygen (PaQ2) less than 8.0 kPa (60 mmHg) with
Source: From Ref. [2] with permission.
or without arterial partial pressure of CO2 (PaCO2) greater than 6.7 kPa (50 mmHg)
while breathing air at sea level.

diseases. This makes dierentiating the diseases sometimes where other risk factors, such as heavy outdoor and indoor/
challenging for the clinician, especially in older adults who occupational air pollution, may be important risk fac-
are or have been smokers. tors that are causally related to COPD [2]. The relation-
The clinician can be guided by information in the clin- ship between asthma and smoking is complex. Individuals
ical history such as smoking history, age of onset of symp- with asthma may be non-smokers, smokers, or ex-smokers.
toms, history of atopic conditions, and description of acute Since asthma genes and genes leading to the susceptibility
episodes of shortness of breath (see Table 1.5). to develop airow obstruction with smoking are common in
Asthma usually has its onset in early childhood. the population, the likelihood that an individual may have
However, adult-onset asthma does exist, and many are una- both is high. Likewise, COPD may occur in lifetime non-
ble to remember childhood events that would provide a clue smokers [1315]. In some, this may be longstanding asthma
to the early stages of asthma. Therefore, unless symptoms that may have been undiagnosed. In others, genes that are
are continuous from childhood, the onset of asthma symp- as yet unrecognized may be responsible. Alpha-1 antitrypsin
toms in adult life may be hard to interpret, especially in the deciency is the model for such a genotype.
presence of other risk factors such as smoking. COPD typi- Pulmonary function tests can also provide guidance.
cally becomes clinically apparent in the sixth and seventh Both diseases are characterized by airow obstruction except
decades of life. If an individual is physically active, he or she in the early or mild stages. In asthma, lung function either
may notice reduced exercise tolerance earlier. remains normal or can be normalized with treatment in
COPD in developed countries is mostly a disease of patients with mild intermittent or mild persistent disease [1].
smokers. This is not necessarily true in developing countries COPD, in comparison with asthma, is dened by irreversible

6
Definitions 1
airow limitation, and this becomes progressively greater
as the disease advances. Lung function in asthma is char- LIMITATIONS OF THE DEFINITIONS
acterized by reversibility and variability. Reversibility refers
to the short-term response to an inhaled bronchodilating Denitions for both asthma and COPD have limitations since
agent, and is preferably measured with spirometry or peak they can reect only our current understanding of the diseases,
ow (acceptable but not as helpful as spirometry). Variability which is quite limited. Both diseases will continue to be rede-
refers to the improvement and deterioration in symptoms ned as our understanding of them deepens, and as new eec-
and lung function over time (both short- and long-time tive preventive strategies and treatments become available.
periods) that is characteristic of asthma. The GINA guide-
lines [1] recommend that reversibility be dened as a 20%
improvement post-bronchodilator in the 1-second forced References
expiratory volume (FEV1) or peak ow (PEF). GINA fur-
ther denes variability as a diurnal variation in PEF of more 1. Global Strategy for the Diagnosis, Management, and Prevention of chronic
than 20% (with twice daily reading, more than 10%). Obstructive Pulmonary Disease. Global Initiative for Chronic Obstructive
Lung Disease (GOLD), 2006; Available from: URL: www.goldcopd.org
The GOLD COPD guidelines [2] recommend that
2. Global Strategy for Asthma Management and Prevention. Global
spirometry be used to establish that the airow limitation is Initiative for Asthma (GOLD), 2006; Available from: URL: www.
not fully reversible (dened as a post-bronchodilator ginasthma.org
FEV1/FVC ratio of 0.7 and FEV1  80% predicted), 3. National Asthma Education and Prevention Program Expert Panel
and to stage the severity of the disease. However, GOLD Report 2: Guidelines for the Diagnosis and Management of Asthma,
emphasizes that bronchodilator reversibility testing does National Institute of Health, National Heart, Lung, and Blood
not predict a patients response to treatment or predict dis- Institute. NIH Publication 974051, 1997.
ease progression. 4. Wenzel SE. Asthma: Dening of the persistent adult phenotypes.
Lancet 368: 80413, 2006.
5. A plea to abandon asthma as a disease concept. Editorial, Lancet
368:705, 2006.
6. Pauwels RA, Buist AS, Calverley MA, Jenkins CR, Hurd SS. Global
OVERLAP BETWEEN ASTHMA AND COPD strategy for the diagnosis, management and prevention of chronic
obstructive pulmonary disease. NHLBI/WHO Global Initiative for
Chronic Obstructive Lung Disease (GOLD) Workshop Summary.
Not acknowledged in the denitions is the fact that long- Am J Respir Crit Care Med 163: 125676, 2001.
standing asthma can lead to airway remodeling and partly 7. Celli BR, MacNee W and committee members, Standards for the
irreversible airow obstruction [16]. So, in many (but not diagnosis and treatment of patients with COPD: A summary of the
all) with longstanding asthma, there is an appreciable com- ATS/ERS position paper. Eur Respir J 23: 93246, 2004.
ponent of chronic irreversible airow obstruction with 8. National Institute for Clinical Excellence (NICE). Chronic obstruc-
reduced lung function and incomplete response (or at least, tive pulmonary disease. National clinical guideline on management of
chronic obstructive pulmonary disease in adults in primary and second-
not complete reversibility) to a short-acting bronchodilator
ary care. Thorax 59(Suppl 1): 1232, 2004.
or to oral or inhaled corticosteroids [17]. This complicates 9. National Institute for Clinical Excellence (NICE) Guideline available
the diagnosis of asthma in older adults, and requires that at URL: www.nice.org.uk/CG012niceguideline
the goals of treatment be modied since maintenance of 10. Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL.
normal lung function can no longer be a realistic goal. Patterns of comorbidities in newly diagnosed COPD and asthma in
Whether longstanding asthma with remodeling can primary care. Chest 128(4): 2099107, 2005.
be called COPD is intensely controversial. In so far as there 11. Agusti AG. Systemic eects of chronic obstructive pulmonary disease.
is irreversible or poorly reversible airow obstruction in the Proc Am Thorac Soc 2(4): 36770, 2005.
remodeled lungs, the term seems appropriate. Conceptually 12. Dodge R, Cline MG, Burrows. B. Comparisons of asthma, emphy-
and practically, the recognition that remodeling is a feature sema, and chronic bronchitis diagnoses in a general population sample.
Am Rev Respir Dis 133: 98186, 1986.
of longstanding asthma in many (but not all) reinforces the
13. Celli BR, Halbert RJ, Nordyke RJ, Schan. B. Airway obstruction in
notion that these diseases constitute a spectrum of disease, never smokers: Results from the Third National Health and Nutrition
as illustrated in Fig. 1.1, ranging from fully reversible to Examination Survey. Am J Med 118: 136472, 2005.
fully irreversible. 14. Menezes AM, Perez-Padilla R, Jardim JR, Muino A, Lopez MV,
Valdivia G et al. Chronic obstructive pulmonary disease in ve Latin
American cities (the PLATINO study): A prevalence study. Lancet
366(9500): 187581, 2005.
EXACERBATIONS 15. Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P,
Mannino DM, Menezes AMB, Sullivan SD, Lee TA, Weiss KB, Jensen
RL, Marks GB, Gulsvik A, Nizankowska-Mogilnicka E. International
The denition of asthma highlights the importance of exac- Variation in the prevalence of chronic obstructive pulmonary disease
(The BOLD Study): a population-based prevalence study. Lancet 2007;
erbations as a feature of asthma, and emphasizes the uctua-
370:74150.
tions of the disease [1, 3]. The denition of COPD does not 16. James AL, Wenzel SE. Clinical relevance of airway remodelling in
include any mention of exacerbations [2, 68]. Nevertheless, airway diseases. Number 4 in Series Airway Remodelling: from Basic
they may be as important in the natural history of COPD as Science to Clinical Practice. Eur Respir J 30: 13455, 2007.
they are in asthma [1] and account for approximately 70% 17. Fish JE, Peters SP. Airway remodeling and persistent airway obstruc-
of the COPD-related costs in the United States [2]. tion in asthma. J Allergy Clin Immunol 104: 50916, 1999.

7
Epidemiology
2
CHAPTER

DEFINING THE DISEASES However, this denition is non-specic


Dawn L. DeMeo and
and does not provide absolute criteria to facili-
tate dierentiating asthma from other airway Scott T. Weiss
Asthma diseases [5].
Beyond denitions, there are dierences Channing Laboratory, Brigham and
The study of asthma epidemiology has been between languages for the words used to describe Womens Hospital, Harvard Medical
plagued by lack of consensus regarding standards asthma symptoms. A novel approach to this School, Boston, MA, USA
for diagnosis. Most denitions have included var- problem has been used in the International Study
iable airow obstruction, but asthma is a clinical of Asthma and Allergies in Children (ISAAC),
syndrome, without a widely accepted case deni- which includes an asthma video questionnaire
tion. Epidemiology studies have used question- demonstrating clinical signs of asthma, as an
naires to assess for the presence of disease, but are attempt to improve uniformity in surveying for
limited by recall and misclassication bias. Some asthma [6]. This multi-modality approach rep-
have suggested that symptoms should be assessed resents an improvement in asthma surveillance
in conjunction with airway hyperresponsiveness and has captured more individuals with asthma.
[1]. Others argue that airway hyperresponsive- However, diagnostic heterogeneity remains, as
ness and symptoms should be analyzed separately even within the ISAAC project, prevalence esti-
owing to the poor correlation between clinical mates of current asthma may vary depending
asthma and hyperresponsiveness [2]. Population- upon the assessment tool used (i.e. video versus
based epidemiology studies have demonstrated a questionnaire).
low sensitivity of airway hyperresponsiveness for
detecting individuals with physician-diagnosed
asthma versus a sensitivity of greater than 90% in Chronic obstructive pulmonary
clinic studies [3]. A standard denition of asthma
is as a chronic inammatory disease of the air-
disease
ways. A commonly referenced formal deni-
COPD includes chronic bronchitis, small airways
tion is that promulgated in the Global Initiative
disease and emphysema, and is characterized by
for Asthma (GINA) guideline, which denes
airway obstruction that is xed or only partially
asthma as
reversible. The diagnosis of COPD attached to
a chronic inammatory disorder of the airways a given patient varies depending on the degree
in which many cells and cellular elements play a of airow obstruction considered diagnostic
role. The chronic inammation causes an associ- within a given set of guidelines. Thus the long-
ated increase in airway hyper-responsiveness standing lack of international standardization of
that leads to recurrent episodes of wheezing, criteria for diagnosis of COPD makes under-
breathlessness, chest tightness and coughing, standing relative incidence and prevalence quite
particularly at night or in the early morning. challenging. This is well illustrated by a study by
These episodes are usually associated with wide- Lindberg et al. [7], who compared COPD prev-
spread but variable airow obstruction that is alence rates using European Respiratory Society
often reversible either spontaneously or with (ERS), British Thoracic Society (BTS), Global
treatment [4]. Initiative for Chronic Obstructive Lung Disease

9
Asthma and COPD: Basic Mechanisms and Clinical Management

(GOLD), and clinical and spirometric American Thoracic Global burden of disease estimates suggest that at least
Society (ATS) criteria. In this study, ERS criteria revealed a 300 million people worldwide have asthma, with the poten-
14.0% prevalence of COPD, BTS criteria 7.6% prevalence, tial for an additional 100 million more cases by the year 2025
GOLD criteria 14.1% prevalence, clinical ATS criteria [15]. In childhood, incidence rates for asthma are highest
12.2% prevalence, and spirometric ATS criteria 34.1%. among the youngest age groups and among male children
This example highlights the diculty of comparison until puberty [1621]. In a study of an adult Swedish popu-
between international studies/standards and the eorts to lation, Toren and Hermansson [22] found the incidence
understand COPD epidemiology on a global scale. Similar rate for adult-onset asthma to be highest among females of
prevalence dierences depending upon reference criteria all ages greater than 20, with an incidence of 1.3 per 1000
have been observed by other authors [8, 9], further highlight- person-years; among women 1620 years of age the rate was
ing the challenges inherent in making comparisons between 3 per 1000 person-years. Analysis of data from a prospec-
populations. tive cohort study in Finland demonstrated no increase in
Recently, an international committee convened to asthma incidence from 1982 to 1990 in adults aged 1845
rene and promote standardization of a COPD denition. years [23]. Early investigation into the increasing preva-
The GOLD has dened COPD as lence of asthma in the United States was noted in a review
of medical records from Olmsted County, Minnesota, where
a preventable and treatable disease with some signicant
the annual incidence of asthma was found to increase from
extra pulmonary eects that may contribute to the severity
183 per 100,000 in 1964 to 284 per 100,000 in 1983. The
in individual patients. Its pulmonary component is char-
most signicant increase was in children aged 114 years,
acterized by airow limitation that is not fully reversible.
suggesting a potential cohort eect early in life. Despite this
The airow limitation is usually progressive and associ-
increased incidence in asthma among children from 1964 to
ated with an abnormal inammatory response of the lungs
1983, constant rates were observed among adults [16].
to noxious particles or gases [10].
Although these data indicate that asthma incidence
GOLD stages are dened using post-bronchodilator has been increasing, minimal information has been available
spirometry, with an FEV1/FVC ratio of less than 0.7 den- for trends in COPD incidence. One challenge of studying
ing the presence of obstruction, and the FEV1 reduction COPD incidence is that the disease is usually moderately
translating into the severity of COPD. A key element of advanced at diagnosis, and thus true incidence rates have
this updated denition is that it includes capturing features remained elusive. However, a recent study observed that cough
of extra-pulmonary co-morbidities which have relevance and phlegm may identify a group at high risk for incident
for disease severity [11]. The GOLD initiative has aimed to COPD [24]. This study by de Marco and colleagues focused
promote studies to understand the increasing prevalence of on a cohort of 5002 subjects without asthma and with nor-
COPD worldwide, as well as to standardize the collection mal lung function. The observed incidence rate of COPD was
of data for international comparison of research [12]. 2.8 cases/1000/year; the incidence rate ratio for chronic cough
In summary, for many years both asthma and COPD and phlegm was 1.85 (95% CI 1.172.93) with a 10-year
have lacked widely accepted case denitions, but international cumulative incidence of COPD in the overall cohort of 2.8%.
eorts have been developed to rectify this. Denitions of both Two other studies have reported on incidence rates of COPD
diseases include both symptoms and spirometric features. using GOLD criteria, with a 10-year cumulative estimate of
Rening the standardization of clinical diagnosis will facili- 13.5% noted by Lindberg et al. [25], and a 9-year cumulative
tate comparability in epidemiological studies. However, given incidence of 6.1% in a study by Johannessen et al. [26].
the wide variability in disease denitions for both diseases,
comparisons of studies of asthma and COPD between popu-
lations and between countries must be viewed in the light of
dierences in criteria used for disease diagnosis. Although
the GINA and GOLD guidelines have brought some stand-
PREVALENCE
ardization and consensus to diagnosing asthma and COPD
respectively, diagnostic heterogeneity remains and further Trends in the prevalence of obstructive lung disease have
renement of these guidelines is an important goal. been suggested by an analysis of the Third National Health
and Nutrition Examination Survey (NHANES III) [27].
This survey included subjects with asthma, chronic bron-
chitis, and emphysema (Fig. 2.1). In this cohort, the case
INCIDENCE denitions were a physician diagnosis of chronic bronchitis,
asthma or emphysema, respiratory symptoms, and low lung
function. Of note, the investigators dened low lung func-
Incidence rates for asthma and COPD vary depending on tion as present when the FEV1/FVC ratio was 0.70 and
the age of the population under consideration. For exam- the FEV1 was less than 80% of predicted. Of the investigated
ple, asthma is commonly diagnosed in early childhood and population of 20,050 adults, 6.8% had low lung function as
COPD is commonly diagnosed after age 60. Interestingly, thus dened; 7.2% of the population had an FEV1/FVC
cases of adult-onset asthma and early-onset COPD pre- ratio less than 0.70 with an FEV1 greater than 80% pre-
dominate in women, suggesting that there may be a common dicted, and were not included as having low lung function.
hormonal inuence on the age-of-onset of these diseases Of the entire population, 8.5% reported obstructive lung
[13, 14]. disease. Importantly, 63.3% of those with documented low

10
Epidemiology 2
25
Current COPD and asthma Current COPD
Current asthma Past chronic bronchitis or asthma

20
People with indicated condition (%)

15

10

5
FIG. 2.1 Age-specific percentage of individuals,
stratified by race and sex, with COPD and
asthma, current COPD, current asthma, and
past chronic bronchitis or asthma. Reproduced
0 from National Center for Health Statistics, Plan
and Operation of the Third National Health and
1724
2544
4564
6574
7584
85

1724
2544
4564
6574
7584
85

1724
2544
4564
6574
7584
85

1724
2544
4564
6574
7584
85
Age Nutrition Examination Survey, 19881994, US
Department of Health and Human Services
Black female Black male White female White male publication PHS 941308, 1994, with permission.

lung function had no current or prior doctor diagnosis of and the main source of prevalence data in adults includ-
obstructive lung disease. In addition to prevalence informa- ing the European Community Respiratory Health Survey
tion regarding low lung function, NHANES III data suggest (ECRHS). Higher prevalences of asthma (10%) have been
that there is still a signicant proportion of disease that goes noted in developed countries including Canada, the United
undiagnosed in the mild stages, leading to an underestima- States, United Kingdom, New Zealand, and The Republic
tion of the true prevalence of obstructive lung disease. of Ireland [15]. In parallel with urbanization, the rates of
asthma have increased in developing countries as well.
The ISAAC has as its aim to describe, across 155
Asthma centers, the prevalence and severity of asthma in children
in 56 countries [6]. Phase 1 of this trial has demonstrated
Data from the United States have suggested an increase in a large variation in the prevalence of asthma symptoms in
prevalence of asthma in children as well as in older adults children throughout the world, with the highest preva-
(Fig. 2.2) [28]. During the last several decades studies have lence in centers from Australia, New Zealand, the United
suggested an increase in prevalence worldwide of 56% Kingdom, and Ireland [3235]. While the prevalence of
per year. Data from the National Health Interview Survey allergic rhinitis has been noted to be scattered in the groups
(NHIS) reveal a 75% increase in self-reported asthma rates with the highest prevalence of asthma, the lowest preva-
from 1980 to 1994. This trend was demonstrated in all age lence for rhinitis has been found in countries where the
and race strata as well as in both genders. The most signi- asthma prevalence was lowest, such as in Eastern Europe,
cant increase demonstrated by the NHIS was among chil- Indonesia, Greece, and India. In addition to dening preva-
dren 04 years of age (increase of 160%) and persons 514 lence rates, the ISAAC study represents an eort to estab-
years of age (increase of 74%) [29]. lish an international standard to facilitate comparability of
Repeatedly, the prevalence of asthma amongst inner- data from epidemiological studies of asthma. The rising
city children has been demonstrated to be much higher asthma prevalence rates in children heralds rising asthma
than among similar aged children living outside the inner rates for adults, as two-thirds of children with asthma still
city [2931]. It has been suggested that a doctors diagno- have symptoms by early adulthood [36].
sis of asthma is made less frequently than asthma symptom
reporting, raising concern that despite increasing prevalence
there is still a tendency to under-diagnose asthma, and con- Chronic obstructive pulmonary disease
sequently underestimate true prevalence values [32].
The GINA project [15] has compiled asthma preva- COPD is best understood by understanding rst the trends
lence data for 20 regions of the world, with the main for smoking in populations. Although projected smoking rates
sources of data in children including the ISAAC project, throughout the world have increased, smoking prevalence in

11
Asthma and COPD: Basic Mechanisms and Clinical Management

Australia Australia
40 United States 40 United States
Canada Switzerland
Switzerland Germany
Germany The Netherlands
35 35
United Kingdom United Kingdom
Norway Sweden
Finland Norway
30 Estonia 30 Estonia

Prevalence of asthma symptoms (%)


Poland Italy
Prevalence of asthma (%)

Italy Spain
25 Spain 25 Singapore
Israel Hong Kong
Singapore Korea
20 Hong Kong 20
Taiwan
Korea
15 15

10 10

5 5

0 0
1965 1970 1975 1980 1985 1990 1995 2000 2005 1965 1970 1975 1980 1985 1990 1995 2000 2005

FIG. 2.2 Changes in the prevalence of asthma and asthma symptoms in children and young adults. Reproduced from Ref. [28], with permission.

the United States has been decreasing. Estimates from the 14.1 million with chronic bronchitis and 1.8 with emphy-
year 2005 suggest that 21% of Americans smoke cigarettes, sema. By these measures, there was no change in the preva-
with cigarette smoking prevalence rates varying by both sex lence of emphysema from 1982 to 1996, although from 1983
and race. Recent prevalence estimates [37] for smoking were to 1995 the prevalence of chronic bronchitis continued to
highest for American Indian/Alaska Natives (37.5% men and increase. In a study of the Canadian population, prevalence
26.8% women). The prevalence of current smoking is 20.0% rates of COPD were 4.6% in the 5564 age group, 5.0% in
in white women, 17.3% in African American women, 24.0% the 6574 age group, and 6.8% in the greater than 75 age
in white men, and 26.7% in African American men. group [41]. These data may be an underestimation, as there
However, in the context of COPD, susceptibility is a suggestion that COPD prevalence rates are underesti-
to cigarette smoke is not uniform and varies as a function mated in the elderly, especially in those with lower incomes
of the amount of cigarette smoking [38]. Stang et al. [39] [42]. By 2001, in distinction to the many asthma prevalence
utilized smoking rates to create a mathematical model for studies, only 32 prevalence surveys of COPD were reported
estimating COPD prevalence. Using their model, they esti- (Fig. 2.3) [9] with comparability somewhat limited by
mated that 15.3 million people in the United States aged COPD case denitions. The Burden of Obstructive Lung
40 years or more have COPD; this was a reasonable esti- Disease (BOLD) project is a large-scale study of COPD,
mate compared to the spirometric prevalence of 17.1 mil- with one goal of measuring COPD prevalence using stand-
lion as estimated by the NHANES III. Using this model, ard GOLD criteria. A recent report from the study in 1258
they also predicted the prevalence of COPD in Germany subjects reported a 26.1% prevalence of at least GOLD
(2.7 million), the United Kingdom (3.0 million), Spain (1.5 Stage 1 COPD, and 10.7% for GOLD Stage 2 or higher
million), Italy (2.6 million), and France (2.6 million), and [44]. Pooled estimates based on GOLD criteria have sug-
suggested smoking rates as a useful surrogate for estimating gested a prevalence of GOLD Stage 1 or higher COPD of
COPD prevalence. 5.5% and 9.8% for GOLD Stage 2 or higher [9].
The World Health Organization prediction is that by COPD is likely under-diagnosed in both North
2020 COPD will rise from being the twelfth to the fth American and European populations. For example, the
most prevalent disease worldwide, and from being the sixth IBERPOC Project (Estudio Epidemiologico de la EPOC
most common cause of death to the third most common en Espaa) was a population-based study of prevalence of
[40]. Prevalence estimates of COPD in the United States in COPD in Spain [45]. The prevalence of COPD in this
1996, before widespread implementation of GOLD criteria, population (26% current smokers, 24% ex-smokers, 76%
indicated approximately 15 million people have COPD with men), dened according to ERS criteria, was 9.1%. Only

12
Epidemiology 2
Prevalence of COPD States; the utilization increase has been concomitant with the
20 documented increase in asthma prevalence [4648].
Increased hospital visits have been documented
Prevalence per 100

15 worldwide, including in England, New Zealand, the United


States, Greece, Australia, and Canada [4956]. In capturing
10 the epidemiology trend from the 1960s to the 1980s, Evans
et al. reported on a 200% increase in rates of hospitaliza-
5
tion of adults with asthma (and a 50% increase for children
with asthma) [57]. Overall, hospitalizations with asthma
as a primary diagnosis increased most steeply in the 1970s
0
25 35 45 55 65 75 85
until the mid-1980s and then remained constant; this is in
contrast to asthma as a secondary diagnosis which increased
Midpoint of age-range of population studied
until 1997. From 1975 to 1995, oce visits for asthma more
Opinion Diagnosis Symptoms Spirometry than doubled, from 4.6 to 10.4 million [29].
Based on the National Ambulatory Medical Care
FIG. 2.3 Prevalence of COPD using estimates from expert opinion, Survey and the National Hospital Ambulatory Medical Care
physician diagnosis symptoms and spirometry. Data from Ref. [9] as Survey, in 1998 more than 14 million visits were made to
reproduced in Ref. [43], with permission. physicians for diagnoses related to COPD, and this was an
increase from 5.5 million visits reported in 1980. In 2000,
there were approximately 726,000 hospitalizations coded
22% of those diagnosed had a prior diagnosis, while 48% as COPD or allied conditions [58]. Care must be taken in
had prior respiratory symptoms. More recently, despite interpretation of these data because of non-uniform case
prevalence estimates for GOLD Stage 1 or higher COPD denitions; more than half of the discharge diagnoses were
in the BOLD study in Salzburg, only 5.6% of subjects non-specically coded as COPD or allied conditions.
reported ever receiving a doctor diagnosis of COPD [44]; In summary, increased health service utilization has
the prevalence has yet to translate into widespread use of occurred for asthma and COPD during the last two decades.
spirometry for COPD screening. Overall, hospital admissions and discharges have increased
The high-prevalence estimates for both asthma and for both diseases.
COPD have translated into signicant morbidity associ-
ated with both diseases. In 2001, asthma was ranked as the
25th leading contributor to disability adjusted life years
(DALYs) worldwide; COPD was ranked 12th. In this con-
text, together with the high-prevalence estimates for both
MORBIDITY AND MORTALITY
disease, the global burden of disease and economic costs for
both diseases are high. Asthma
In summary, the prevalences of both asthma and
COPD are increasing in both Western developed and devel- The New Zealand epidemic of asthma in the 1970s prompted
oping countries. As both asthma and COPD are both likely a review of asthma deaths in Western countries; among such
under-diagnosed, the prevalence estimates underestimate the countries there was a notable increase of 1.5- to 2-fold in the
true burden of these diseases. Variability in denitions of both asthma mortality rates between the mid-1970s and the mid-
asthma and COPD contribute to inexact prevalence estimates 1980s [59]. The highest mortality rates in the United States
and problems with comparisons of prevalence data. ISAAC have been in the inner-city regions, with particularly high-
(for childhood asthma), ECRHS (for adult asthma), and risk populations studied in East Harlem, New York City,
GOLD (for COPD) represent international eorts under- and Cook County, Chicago [31, 60]. One study observed
way to standardize the denitions used in studies to enhance that socioeconomic and racial disparities were attributable to
comparisons of incidence, prevalence, and burden of disease. higher incidence of asthma exacerbations among inner-city
children, with no excess utilization of medical resources [61].
International comparisons of mortality rates have
been limited by dierences in recording statistics of cause of
HEALTHCARE UTILIZATION AND death [62]. There is variability in the mortality rates ascribed
HOSPITALIZATION TRENDS to asthma, with signicant variation by region of the world
(Fig. 2.4), with the highest asthma case fatality rates in
China (36.7/100,000 asthmatics) [15]. Mortality rates for
In the United States, the estimated cost for year 2000 for asthma have decreased over the past 20 years, likely due to
asthma was projected to be 12.7 billion dollars (8.1 for direct improvements in pharmacotherapy, although it has been sug-
cost, 2.6 related to morbidity, 2.0 related to mortality) and 30.4 gested that most deaths from asthma now occur in adults,
billion dollars for COPD (14.7 for direct cost, 6.5 related to potentially consequent to medical non-compliance [63].
morbidity, 9.2 related to mortality). Utilization of health serv- Comparison of mortality rates is dicult also because of the
ices has continued to increase for both diseases. An increase lack of standardized denitions for the disease, and because
in health service use has been documented in many countries, of environmental, genetic, socioeconomic, and occupational
including the United Kingdom, Canada, and the United inuences unique to a given population.

13
Asthma and COPD: Basic Mechanisms and Clinical Management

Countries shaded according to case fatality rate (per 100,000 asthmatics)

10.0 05.0 5.110.0 No standardized data available

FIG. 2.4 Asthma case fatality rate in individuals 534 years of age calculated as the number of deaths per 100,000 cases of asthma. Reproduced from Ref. [15],
with permission.

Rate/100,000 population Rate/100,000 population


40 30 20 10 0 0 10 20 30 40 50 60 70 80
Hungary (95)
Ireland (95)
Romania (96)
Scotland (97)
New Zealand (94)
United Kingdom (97)
England/Wales (97)
United States (97)
Northern Ireland (97)
Australia (95)
Spain (95)
Poland (96)
The Netherlands (95)
Germany (97)
Bulgaria (94)
Portugal (96)
Norway (95)
Canada (95)
Austria (97)
Italy (93)
France (95)
Sweden (96)
Israel (95)
Japan (94) Women Men
Greece (96)

FIG. 2.5 Age-adjusted death rates for COPD by country and sex, for individuals aged 3577. The year of data is shown in parentheses. Reproduced from Ref.
[12], with permission.

Chronic obstructive pulmonary disease [64]. In longitudinal follow-up of 13,756 individuals in the
Atherosclerosis Risk in Communities (ARIC) study, rapid
Since 1960 mortality associated with COPD has continued lung function decline over a 3-year period was associated
to rise. In the year 2000, the number of women who died with an increased risk for COPD-related hospitalization
from COPD surpassed the number of men [58], and stand- and death [65].
ardized mortality rates have been observed to be higher in International mortality trends demonstrate high rates
women versus men with COPD (4.8 versus 2.7 respectively) of deaths for COPD in many countries. These dierences
14
Epidemiology 2
may be accounted for in part by dierent smoking behav- 8% reduction in FEV1. The Vlagtwedde/Vlaardingen study
iors, which include tobacco type, along with other environ- [68] demonstrated a large eect of cigarette smoking in
mental, infectious, and genetic factors. Dierences among decreasing maximal lung function in individuals less than
these death rates are striking (Fig. 2.5), but again lack of age 20; this eect exceeded the eect of cigarette smoking
standardization in coding practices and death certication on lung function decline seen in older subjects.
as well as practice dierences and quality of care are rele- Smoking is a notable risk factor for both asthma and
vant when comparing estimates [12]. COPD in children and adults, and active smoking perpetu-
Although overall asthma mortality remains low com- ates pulmonary (and likely systemic) inammation. Overall,
pared with COPD, mortality rates for both asthma and smoking is associated with an increase in asthma incidence
COPD have increased in the last decade. Dierences in [69, 70], as well as an increased symptom severity, increased
death rates for asthma and COPD between countries are morbidity and lung function decline, and an increased
multifactorial (genetic, environmental, occupational, socioe- risk of death [7174]. Passive exposure to cigarette smoke
conomic), but dierential coding of cause-of-death statistics increases the risk for the development of asthma and allergic
hinders accuracy of estimates for both diseases. sensitization [7577]. There has also been a suggestion that
non-specic airways responsiveness is increased by environ-
mental and personal smoke exposure [78].
SMOKING Maternal smoking is a risk factor for the development
of asthma in children up to 1 year of age [79]. In a case-
control study of children whose mothers were heavy smok-
Burrows and colleagues [38] have demonstrated that, ers, one group demonstrated an odds ratio of 2.15 among
for a given level of tobacco smoke exposure, FEV1 varies 34-year olds for the development of asthma; these data
substantially (Fig. 2.6). In addition, the doseeect relation- were controlled for family history, past infections, gender,
ship between cigarette smoking and FEV1 decline depends and other demographic variables [80]. In a 6-year follow-up,
on the year of life when an individual is exposed. Dose and the odds ratio for asthma among those exposed to maternal
timing of tobacco smoke exposure have a dierential eect smoking was 3.8 [81].
on FEV1 depending on the stage of the life cycle (Table 2.1). As noted above, the single most signicant risk fac-
Cunningham et al. [66] observed that maternal smoking tor for COPD is tobacco smoking. Although an oft quoted
during pregnancy resulted in a 1.3% reduction in FEV1 when estimate is that only 1015% of smokers actually go on to
children were 812 years old. Tager et al. [67] found that develop obstructive lung disease, this is a marked underes-
adolescents who smoke when aged 1520 have an estimated timate, with many researchers suggesting that all individuals

0 pack-years 1 S.D. Mean 1 S.D.


20
10
Median
0
020 pack years
20
10
0
% of Population

2140 pack years


20
10
0
4160 pack years
20
10
0
61 pack years
20
10
0

40 60 80 100 120 140 160


% FEV1

FIG. 2.6 Distribution of percentage predicted forced expiratory volume in 1 s (FEV1) in adults with varying smoking histories as measured in pack-years. The
proportion of smokers with normal flow decreased with increasing pack-year histories. Yet, many have near-normal FEV1 with extensive smoking history.
Subjects with respiratory trouble before age 16 were excluded. Medians and means 1 SD are shown for each group in the abscissae. Note that among the
425 persons with 20 pack-years, only 15% have an FEV1 of 60% of predicted or less. Reproduced from Ref. [38], with permission.

15
Asthma and COPD: Basic Mechanisms and Clinical Management

TABLE 2.1 Effects of cigarette smoking at different stages of the life cycle. immunoglobulin by sensitized lymphocytes. Elevations in
specic IgE and/or total IgE, total eosinophil counts, and
FEV1 reduction skin test reactivity to specic allergens have been used clini-
Life phase Total FEV1 (ml/year per cally to detect allergic individuals. As measured by skin test
(gender) Cigarette dose reduction packs/day) reactivity, allergy increases with age until about age 15, at
which point it is maximal. The decline in skin test reactivity
In utero Variable exposure 27.3 mla 36
after age 35 confounds the measurement of this phenotype
(M and F) for 9 months
in older individuals. This reported association between skin
Adolescence 15 cigarettes/day 390 ml 104 test reactivity and decline in FEV1 is not consistent in the
(M) for 5 yearsb literature. In retrospective studies, Taylor et al. [87] and Frew
et al. [88] demonstrated no relation of skin test positivity to
Adolescence 10 cigarettes/day 340 ml 136 decline in FEV1. However, Gottlieb et al. [89] investigated
(F) for 5 yearsb this prospectively in the Normative Aging Study and found
Adult (M) Variable N/A 13c
that skin test positivity predicted increased annual rates of
decline in both FEV1 and FEV1/FVC ratio.
Adult (F) Variable N/A 7c Allergic inammation is characteristic of asthma;
8090% of childhood asthmatics are atopic, and the degree
Source: Adapted from Weiss ST, Silverman EK. Risk factors for the development of chronic
of atopy appears to be associated with prognosis in child-
obstructive pulmonary disease. In: Severe Asthma, New York: Marcel Dekker, 2000.
hood asthma [90]. Studies have demonstrated that the asth-
Notes: M: male; F: female.
a
Adjusted for gender and maternal smoking in the past year; based on 1.3% reduction
matic phenotype is associated with elevated serum IgE levels
and mean FEV1 2.1 l, 1 pack/day in smoking mothers during pregnancy is assumed more so than skin test positivity [91], and that increased air-
for relative FEV1 reduction (Ref. [65]). ways responsiveness is related to total serum IgE levels [92].
b
Median values for cigarette smoking (Ref. [66]). Weiss has suggested that immediate type I hyper-
c
Estimated values (Ref. [67]). sensitivity is a risk factor for the development of chronic
obstructive lung disease, and suggests that atopy may inu-
ence childhood asthma and limit maximal lung function,
accelerate FEV1 decline, and potentially enhance interaction
who smoke will go on to develop COPD. Among those with cigarette smoking to result in FEV1 decline progressing
smokers already with a decreased FEV1, lung injury and sub- to the development of COPD [93]. Hargreave and Leigh
sequent decrements in lung function secondary to cigarette [94] demonstrated, in a subset of COPD patients, that eosi-
smoking are more dramatic. In the Lung Health Study, nophilic inammation is important in COPD exacerbations,
middle-aged smokers (with FEV1 between 55% and 90%) and potentially leads to a decline in lung function. As well,
who continued smoking for 5 years had further losses of an inverse association of serum IgE with the FEV1/FVC
several hundred milliliters of FEV1 [82]. However, COPD ratio has been observed [95]. These data indicate that aller-
has been identied in non-smokers as well. Prevalence has gen sensitization may represent an intermediate phenotype
been noted to increase with age, to be higher in women which needs to be considered in understanding disease onset
than in men, to be particularly high in Hispanic individuals, and progression in both asthma and COPD.
and to be higher in low income versus auent individuals
[83]. Recent data from NHANES III suggests that 25% of
cases of COPD in the United States occurs in lifelong non- Airways responsiveness
smokers [84], a nding that is echoed by estimates of 23%
in the United Kingdom [85] and 23% in Spain [86]. These Airways responsiveness to methacholine and histamine has
observations reinforce that although cigarette smoking is the been used in population-based studies to help dene indi-
most important risk factor for COPD, it is not necessary for viduals susceptible to the development of obstructive lung
the development of irreversible airow obstruction. disease. This intermediate phenotype is a feature of both
In summary, smoking has a lifetime inuence on asthma and a subset of patients with COPD. Baseline levels
asthma and COPD. This starts in utero and continues into of lung function, allergy, age, and cigarette smoking history
older age. Smoking is associated with enhanced airway all inuence airways responsiveness.
responsiveness, both in asthma and COPD. Smoking is suf- Airways hyperresponsiveness has been demonstrated to
cient but not necessary for the development of COPD. predict accelerated decline in lung function and the develop-
Smoking is only one of several risk factors for asthma. ment of COPD [96]. More recently, airways responsiveness
has been demonstrated to predict COPD mortality [97].
Airways responsiveness has been demonstrated to pre-
dict the development of asthma [98]. The prevalence of air-
INTERMEDIATE PHENOTYPES way hyperresponsiveness exceeds the prevalence of asthma;
the former is about 20% in the general population. Data
from the Childhood Respiratory Disease Study demonstrate
Allergy that increased airway responsiveness predicts the develop-
ment of asthma in children and young adults with a 2- to 3-
Allergy represents immediate hypersensitivity to an antigen fold risk [99]. Some have observed this risk to be increased
and is associated with an increased production of a specic as much as 5-fold [100].

16
Epidemiology 2
Airways hyperresponsiveness in COPD patients may more susceptible to develop severe early-onset COPD [14],
be demonstrated in more than two-thirds of individuals in have worse quality of life [114], and higher mortality from
situations where it is actually measured [101]. Some individ- COPD [115] than men. These gender/sex dierences most
uals who develop COPD have an allergic asthma phenotype, likely represent inuences of both dose of tobacco exposure
as suggested by the Dutch hypothesis [102]. Alternatively and underlying genetic and hormonal susceptibilities, and is
the hyperresponsiveness may be a consequence of COPD. a topic of active research.
Results from a 25-year longitudinal study in the Netherlands In summary, in the adult years women have a higher
revealed that increased airways responsiveness is an inde- prevalence of asthma. The prevalence of COPD in women
pendent risk factor for FEV1 decline [103]. Among individu- is increasing, in keeping with the historical trends of ciga-
als with early-onset COPD, the degree of baseline airways rette smoking and disease. The gender and sex dierences
responsiveness determined the response to cigarette smoking; between asthma and COPD highlight the importance of
those with early-onset COPD who have increased airways hormonal and genetic inuences relevant to disease expres-
responsiveness appeared more sensitive to the eects of ciga- sion in men versus women.
rette smoke and had an accelerated decline in FEV1 [104].
Thus, airway hyperresponsiveness, together with features of
allergy and smoking, likely represent common risk factors for
both asthma and COPD. DEMOGRAPHICS

Gender/sex-related influences In the United States, morbidity from asthma has been
demonstrated in multiple studies to be greater in children of
The impact of gender and sex-biology-related features on African American descent. In the United States, physician-
airway disease are complex, and include both social para- diagnosed asthma has been reported in 13.4% of African
digms (gender-related) as well as hormonal and genetic (sex- American children and 9.7% of white children [116].
related) inuences. African American children have also been reported to have
The epidemiology of asthma is characterized by age- greater limitation on activity due to asthma, with more hos-
related sex dierences. Asthma and wheezing have been pital admissions and fewer doctors visits when compared
demonstrated to be more prevalent in young boys than with white children [117]. Mortality from asthma has been
young girls [20]. This trend disappears during puberty [105]. higher for African American children when compared
A recent analysis of the European Respiratory Health Survey with children of other races since the mid-1980s [47, 57,
[106] found that girls had a lower risk of developing asthma 118121]. Data from the NHANES II and the Hispanic
than did boys during childhood; about the time of puberty Health and Nutrition Survey have noted that the preva-
the risk was equal. After puberty, the risk in young women lence of childhood asthma was higher in children of Puerto
was higher than in young men, and this was a consistent Rican versus African American descent (20.1% versus 9.1%
trend in the 16 countries included in this study. respectively) [122]. An extensive review on the topic has
Women older than 20 years have higher prevalence noted that amongst the dierent ethnic groups living in the
and morbidity rates from asthma, and women are more like United States, the prevalence of asthma is highest in Puerto
to present to the emergency department and be admitted Ricans [123].
with a diagnosis of asthma [107, 108]. In the multicenter Studies in Chicago have demonstrated socioeconomic
Asthma Collaboration Study [109], women were more likely gradients and diering outcomes by race. In 1996, asthma
to be admitted to the hospital and report ongoing symptoms hospitalization rates were more than twice as high as the
at follow-up, although overall men had less outpatient care United States rates overall. Age-adjusted mortality was 4.7
and lower pulmonary function. Although it is unclear why times higher in non-Hispanic African Americans than in
women have more severe disease and higher mortality from non-Hispanic whites [124]. An association with poverty has
asthma, hormonal, genetic, environmental, and social factors been suggested [125], and it has also been suggested that
are likely contributory [110]. severe asthma may occur more frequently in poorer com-
For many years COPD has traditionally been con- munities [126, 127]. The association of lower socioeconomic
sidered a disease of men, as men have been noted to have status with increased asthma prevalence is most likely mul-
a higher prevalence of COPD at the population level. Yet, tifactorial: the eects of indoor air pollution, passive ciga-
Prescott et al. [111] have suggested that women are more rette smoke exposure, allergen exposure, and reduced access
susceptible to the development of COPD, and observed to medical care may all be relevant.
that smoking was associated with a greater decrement in Some have suggested, based on the use of education
FEV1 per pack-year of cigarette smoked, when compared as a surrogate for lower socioeconomic status, that there is
to male smokers. Mannino et al. [112] analyzed data for an association of socioeconomic status with the develop-
deaths from obstructive lung disease from 1979 until 1993 ment of obstructive lung disease. Bakke et al. [128] dem-
and found that the mortality rates for men with COPD onstrated that completion of only primary schooling was
have started to stabilize but were continuing to increase associated with an odds ratio of 2.9 for the development
among women, likely reecting smoking trends. In the year of obstructive lung disease when compared with those who
2000, the number of women dying from COPD has sur- achieved university level education. Exposure to smoking
passed the number of men. Women have been observed to and occupational hazards decreased with increasing educa-
be more susceptible to the eects of tobacco smoking [113], tional status.

17
Asthma and COPD: Basic Mechanisms and Clinical Management

that individuals cannot have both reversible and xed airow


AGE obstruction, and hence asthma and COPD at the same time.
The importance of early life and in utero events for the
Infants born prematurely, when compared to those born at subsequent development of disease is a theme that is com-
term, have a risk for asthma that is increased approximately mon to a variety of complex traits. These same issues also
4-fold [129]; reduced lung function measured with birth has present themselves with disorders of the airways. The major
been associated with incident asthma by age 10 [130]. There barrier to applying a life-cycle approach to disease risk fac-
are data that breastfeeding is protective against asthma and, tors and natural history relates to the problem of recall bias
as previously noted, the risk for asthma increases in chil- and potentially missing or inadequate information about
dren exposed to cigarette smoke both in utero and during past events in both childhood and adult life, which may
childhood. Asthma that begins after age 50 is thought to be then distort the clinical picture. It is only through careful
more severe and less reversible than asthma that is incident analysis of longitudinal cohort data that the true history of
in childhood [131]. In childhood, the remission of asthma the relationship between the major environmental expo-
before adulthood has been suggested to be about 50% [69, sures and disease natural history can be deduced. We need
132, 133]. Less information is available on the epidemi- to continue to gather such data, particularly data to link
ology of asthma in the middle-aged and elderly, yet some childhood asthma with adult COPD.
suggest that older patients are more severely aected than
younger patients [134].
Some data support the proposition that individuals References
may outgrow asthma (with remission rates decreasing with
increasing age) [135]. Other data suggest that remission of 1. Toelle BG, Peat JK, Salome CM, Mellis CM, Woolcock AJ. Toward a
denition of asthma for epidemiology. Am Rev Respir Dis 146(3): 633
asthma and respiratory symptoms are uncommon [136].
37, 1992.
Aging has been associated with increased airway obstruc- 2. Pekkanen J, Pearce N. Dening asthma in epidemiological studies.
tion overall [137] and asthma is a risk factor for COPD in Eur Respir J 14(4): 95157, 1999.
adult lifetime never smokers [84]. The association of aging 3. Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyper-
with the development of COPD most likely represents the reactivity. Am Rev Respir Dis 121(2): 389413, 1980.
cumulative insult of a lifetime of smoking and environmen- 4. Global Initiative for Asthma. Global strategy for asthma management
tal exposure interacting with a susceptible host. and prevention. Bethesda, MD: NHLBI/WHO Workshop Report,
2004.
5. Hargreave FE, Parameswaran K. Asthma, COPD and bronchitis are
just components of airway disease. Eur Respir J 28(2): 26467, 2006.

CONCLUSION 6. Asher MI, Keil U, Anderson HR et al. International Study of Asthma


and Allergies in Childhood (ISAAC): Rationale and methods. Eur
Respir J 8(3): 48391, 1995.
7. Lindberg A, Jonsson AC, Ronmark E, Lundgren R, Larsson LG,
Ninety percent of all childhood asthma is diagnosed before
Lundback B. Prevalence of chronic obstructive pulmonary disease
the age of 6 years. Since there is a crude inverse relationship according to BTS, ERS, GOLD and ATS criteria in relation to doc-
between respiratory symptoms and level of lung function, it tors diagnosis, symptoms, age, gender, and smoking habits. Respiration
is not surprising that as lung function increases in childhood 72(5): 47179, 2005.
respiratory symptoms decrease and often disappear. Thus, 8. Viegi G, Pedreschi M, Pistelli F et al. Prevalence of airways obstruction
a large number of individuals are left with the intermedi- in a general population: European Respiratory Society vs American
ate phenotypes of increased airways responsiveness and/or Thoracic Society denition. Chest 117(5 Suppl 2): 339S345S, 2000.
allergy at the time that they reach their maximally attained 9. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino
level of lung function between the ages of 15 and 30. These DM. Global burden of COPD: Systematic review and meta-analysis.
intermediate phenotypes represent denable host character- Eur Respir J 28(3): 52332, 2006.
10. Global Initiative for Chronic Obstructive Lung Disease. A collabora-
istics that confer increased susceptibility to a variety of envi-
tive project of the National Heart, Lung and Blood Institute and the
ronmental exposures encountered in adult life, such as viral World Health Organization. National Institutes of Health, National
respiratory illness, occupation, allergen exposure, and perhaps Heart, Lung and Blood Institute, 2006; Accessed June 30, 2007, at
most importantly, cigarette smoking. www.goldcopd.com.
The most clearly dened (non-genetic) susceptibility 11. Celli BR, Cote CG, Marin JM et al. The body-mass index, airow
factors for premature or early-onset COPD are cigarette obstruction, dyspnea, and exercise capacity index in chronic obstructive
smoking, childhood asthma, increased airways responsive- pulmonary disease. N Engl J Med 350(10): 100512, 2004.
ness, and allergy. It is now clear that most airways hyperre- 12. Hurd SS. International eorts directed at attacking the problem of
sponsiveness in adults antedates, precedes, and predicts the COPD. Chest 117(5 Suppl 2): 336S338S, 2000.
development of COPD. Obviously, this construct suggests 13. Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex
steroid hormones and asthma and wheeze in young women. J Allergy
that most genes that predict susceptibility to asthma may
Clin Immunol 117(5): 10017, 2006.
also be important genetic predictors of COPD susceptibil- 14. Silverman EK, Weiss ST, Drazen JM et al. Gender-related dierences
ity, and this is a topic of ongoing research. in severe, early-onset chronic obstructive pulmonary disease. Am J
Both asthma and COPD are dened as syndromes, Respir Crit Care Med 162(6): 215258, 2000.
and the denitions are loose; thus it is not surprising that 15. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma:
there is substantial overlap between the conditions at any Executive summary of the GINA Dissemination Committee report.
given age. Indeed, there are no substantive data to suggest Allergy 59(5): 46978, 2004.

18
Epidemiology 2
16. Yunginger JW, Reed CE, OConnell EJ, Melton LJ, OFallon WM, year-old children from 9 Spanish populations. The Spanish Group of
Silverstein MD. A community-based study of the epidemiology the ISAAC Study (International Study of Asthma and Allergies in
of asthma. Incidence rates, 19641983. Am Rev Respir Dis 146(4): Childhood). (published erratum appears in Med Clin (Barc) 112(13):494,
88894, 1992. April 17, 1999)]. Med Clin (Barc) 112(5): 17175, 1999.
17. McWhorter WP, Polis MA, Kaslow RA. Occurrence, predictors, and 36. Gerritsen J, Koeter GH, Postma DS, Schouten JP, Knol K. Prognosis
consequences of adult asthma in NHANESI and follow-up survey. of asthma from childhood to adulthood. Am Rev Respir Dis 140(5):
Am Rev Respir Dis 139(3): 72124, 1989. 132530, 1989.
18. Broder I, Higgins MW, Mathews KP, Keller JB. Epidemiology of asthma 37. Centers for Disease Control and Prevention. Tobacco use among adults
and allergic rhinitis in a total community, Tecumseh, Michigan. III. United States, 2005. MMWR Morb Mortal Wkly Rep 55(42): 11458, 2006.
Second survey of the community. J Allergy Clin Immunol 53(3): 12738, 38. Burrows B, Knudson RJ, Cline MG, Lebowitz MD. Quantitative rela-
1974. tionships between cigarette smoking and ventilatory function. Am Rev
19. Broder I, Higgins MW, Mathews KP, Keller JB. Epidemiology of Respir Dis 115(2): 195205, 1977.
asthma and allergic rhinitis in a total community, Tecumseh, Michigan. 39. Stang P, Lydick E, Silberman C, Kempel A, Keating ET. The preva-
IV. Natural history. J Allergy Clin Immunol 54(2): 10010, 1974. lence of COPD: Using smoking rates to estimate disease frequency in
20. Dodge RR, Burrows B. The prevalence and incidence of asthma and the general population. Chest 117(5 Suppl 2): 354S359S, 2000.
asthma-like symptoms in a general population sample. Am Rev Respir 40. Lopez AD, Murray CC. The global burden of disease, 19902020.
Dis 122(4): 56775, 1980. Nat Med 4(11): 124143, 1998.
21. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, 41. Lacasse Y, Brooks D, Goldstein RS. Trends in the epidemiology of
Morgan WJ. Asthma and wheezing in the rst six years of life. The COPD in Canada, 1980 to 1995. COPD and Rehabilitation Committee
Group Health Medical Associates. N Engl J Med 332(3): 13338, 1995. of the Canadian Thoracic Society. Chest 116(2): 30613, 1999.
22. Toren K, Hermansson BA. Incidence rate of adult-onset asthma in 42. Enright PL, Kronmal RA, Higgins MW, Schenker MB, Haponik EF.
relation to age, sex, atopy and smoking: A Swedish population-based Prevalence and correlates of respiratory symptoms and disease in the
study of 15813 adults. Int J Tuberc Lung Dis 3(3): 19297, 1999. elderly. Cardiovascular Health Study. Chest 106(3): 82734, 1994.
23. Huovinen E, Kaprio J, Laitinen LA, Koskenvuo M. Incidence and prev- 43. Mannino DM. Epidemiology and global impact of chronic obstructive
alence of asthma among adult Finnish men and women of the Finnish pulmonary disease. Semin Respir Crit Care Med 26(2): 20410, 2005.
Twin Cohort from 1975 to 1990, and their relation to hay fever and 44. Schirnhofer L, Lamprecht B, Vollmer WM et al. COPD prevalence
chronic bronchitis. Chest 115(4): 92836, 1999. in Salzburg, Austria: Results from the Burden of Obstructive Lung
24. de Marco R, Accordini S, Cerveri I et al. Incidence of chronic obstruc- Disease (BOLD) Study. Chest 131(1): 2936, 2007.
tive pulmonary disease in a cohort of young adults according to the 45. Sobradillo V, Miravitlles M, Jimenez CA et al. [Epidemiological study
presence of chronic cough and phlegm. Am J Respir Crit Care Med of chronic obstructive pulmonary disease in Spain (IBERPOC):
175(1): 3239, 2007. Prevalence of chronic respiratory symptoms and airow limitation].
25. Lindberg A, Jonsson AC, Ronmark E, Lundgren R, Larsson LG, Arch Bronconeumol 35(4): 15966, 1999.
Lundback B. Ten-year cumulative incidence of COPD and risk factors for 46. Fleming DM, Crombie DL. Prevalence of asthma and hay fever in
incident disease in a symptomatic cohort. Chest 127(5): 154452, 2005. England and Wales. BMJ (Clin Res Ed) 294(6567): 27983, 1987.
26. Johannessen A, Omenaas E, Bakke P, Gulsvik A. Incidence of GOLD- 47. Gerstman BB, Bosco LA, Tomita DK, Gross TP, Shaw MM.
dened chronic obstructive pulmonary disease in a general adult popu- Prevalence and treatment of asthma in the Michigan Medicaid patient
lation. Int J Tuberc Lung Dis 9(8): 92632, 2005. population younger than 45 years, 19801986. J Allergy Clin Immunol
27. Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung dis- 83(6): 103239, 1989.
ease and low lung function in adults in the United States: Data from 48. Manfreda J, Becker AB, Wang PZ, Roos LL, Anthonisen NR. Trends
the National Health and Nutrition Examination Survey, 19881994. in physician-diagnosed asthma prevalence in Manitoba between 1980
Arch Intern Med 160(11): 168389, 2000. and 1990. Chest 103(1): 15157, 1993.
28. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 49. Mitchell EA. International trends in hospital admission rates for
55(21): 222635, 2006. asthma. Arch Dis Child 60(4): 37678, 1985.
29. Mannino DM, Homa DM, Pertowski CA et al. Surveillance for asthma 50. Anderson HR, Bailey P, West S. Trends in the hospital care of acute
United States, 19601995. Mor Mortal Wkly Rep CDC Surveill Summ childhood asthma 19708: A regional study. BMJ 281(6249): 119194,
47(1): 127, 1998. 1980.
30. Crain EF, Weiss KB, Bijur PE, Hersh M, Westbrook L, Stein RE. An 51. Jackson RT, Mitchell EA. Trends in hospital admission rates and
estimate of the prevalence of asthma and wheezing among inner-city drug treatment of asthma in New Zealand. N Z Med J 96(740):
children. Pediatrics 94(3): 35662, 1994. 72830, 1983.
31. Persky VW, Slezak J, Contreras A et al. Relationships of race and socio- 52. Halfon N, Newacheck PW. Trends in the hospitalization for acute
economic status with prevalence, severity, and symptoms of asthma in childhood asthma, 197084. Am J Public Health 76(11): 130811, 1986.
Chicago school children. Ann Allergy Asthma Immunol 81(3): 26671, 53. Priftis K, Anagnostakis J, Harokopos E, Orfanou I, Petraki M, Saxoni-
1998. Papageorgiou P. Time trends and seasonal variation in hospital admis-
32. Sole D, Yamada E, Vana AT, Costa-Carvalho BT, Naspitz CK. sions for childhood asthma in the Athens region of Greece: 197888.
Prevalence of asthma and related symptoms in school-age children Thorax 48(11): 116869, 1993.
in Sao Paulo, Brazil International Study of Asthma and Allergies in 54. Carman PG, Landau LI. Increased paediatric admissions with asthma in
Children (ISAAC). J Asthma 36(2): 20512, 1999. Western Australia a problem of diagnosis?. Med J Aust 152(1): 2326,
33. Asher MI, Weiland SK. The International Study of Asthma and 1990.
Allergies in Childhood (ISAAC). ISAAC Steering Committee. Clin 55. Kun HY, Oates RK, Mellis CM. Hospital admissions and attendances
Exp Allergy 28(Suppl 5): 5266, 1998. discussion 901 for asthma a true increase? Med J Aust 159(5): 31213, 1993.
34. Duhme H, Weiland SK, Rudolph P, Wienke A, Kramer A, Keil U. 56. Wilkins K, Mao Y. Trends in rates of admission to hospital and death
Asthma and allergies among children in West and East Germany: A from asthma among children and young adults in Canada during the
comparison between Munster and Greifswald using the ISAAC phase 1980s. Can Med Assoc J 148(2): 18590, 1993.
I protocol. International Study of Asthma and Allergies in Childhood. 57. Evans Rd, Mullally DI, Wilson RW et al. National trends in the mor-
Eur Respir J 11(4): 84047, 1998. bidity and mortality of asthma in the US. Prevalence, hospitalization
35. Aguinaga Ontoso I, Arnedo Pena A, Bellido J, Guillen Grima F, Suarez and death from asthma over two decades: 19651984. Chest 91(6
Varela MM. [The prevalence of asthma-related symptoms in 1314- Suppl): 65S74S, 1987.

19
Asthma and COPD: Basic Mechanisms and Clinical Management

58. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic the rate of decline of FEV1. The Lung Health Study. JAMA 272(19):
obstructive pulmonary disease surveillance United States, 19712000. 1497505, 1994.
MMWR Surveill Summ 51(6): 116, 2002. 83. Whittemore AS, Perlin SA, DiCiccio Y. Chronic obstructive pulmo-
59. Jackson R, Sears MR, Beaglehole R, Rea HH. International trends in nary disease in lifelong nonsmokers: Results from NHANES. Am J
asthma mortality: 1970 to 1985. Chest 94(5): 91418, 1988. Public Health 85(5): 7026, 1995.
60. Carr W, Zeitel L, Weiss K. Variations in asthma hospitalizations and 84. Behrendt CE. Mild and moderate-to-severe COPD in nonsmokers:
deaths in New York City. Am J Public Health 82(1): 5965, 1992. Distinct demographic proles. Chest 128(3): 123944, 2005.
61. McConnochie KM, Russo MJ, McBride JT, Szilagyi PG, Brooks AM, 85. Birring SS, Brightling CE, Bradding P et al. Clinical, radiologic, and
Roghmann KJ. Socioeconomic variation in asthma hospitalization: induced sputum features of chronic obstructive pulmonary disease in
Excess utilization or greater need?. Pediatrics 103(6): e75, 1999. nonsmokers: A descriptive study. Am J Respir Crit Care Med 166(8):
62. Thom TJ. International comparisons in COPD mortality. Am Rev 107883, 2002.
Respir Dis 140(3 Pt 2): S2734, 1989. 86. Pena VS, Miravitlles M, Gabriel R et al. Geographic variations in
63. Burr ML, Davies BH, Hoare A et al. A condential inquiry into prevalence and underdiagnosis of COPD: Results of the IBERPOC
asthma deaths in Wales. Thorax 54(11): 98589, 1999. multicentre epidemiological study. Chest 118(4): 98189, 2000.
64. Ringbaek T, Seersholm N, Viskum K. Standardised mortality rates 87. Taylor RG, Joyce H, Gross E, Holland F, Pride NB. Bronchial reac-
in females and males with COPD and asthma. Eur Respir J 25(5): tivity to inhaled histamine and annual rate of decline in FEV1 in male
89195, 2005. smokers and ex-smokers. Thorax 40(1): 916, 1985.
65. Mannino DM, Reichert MM, Davis KJ. Lung function decline and 88. Frew AJ, Kennedy SM, Chan-Yeung M. Methacholine responsiveness,
outcomes in an adult population. Am J Respir Crit Care Med 173(9): smoking, and atopy as risk factors for accelerated FEV1 decline in
98590, 2006. male working populations. Am Rev Respir Dis 146(4): 87883, 1992.
66. Cunningham J, Dockery DW, Speizer FE. Maternal smoking during 89. Gottlieb DJ, Sparrow D, OConnor GT, Weiss ST. Skin test reactivity
pregnancy as a predictor of lung function in children. Am J Epidemiol to common aeroallergens and decline of lung function. The Normative
139(12): 113952, 1994. Aging Study. Am J Respir Crit Care Med 153(2): 56166, 1996.
67. Tager IB, Munoz A, Rosner B, Weiss ST, Carey V, Speizer FE. Eect 90. Nelson HS. The importance of allergens in the development of asthma
of cigarette smoking on the pulmonary function of children and ado- and the persistence of symptoms. J Allergy Clin Immunol 105(6 Pt 2):
lescents. Am Rev Respir Dis 131(5): 75259, 1985. S628S632, 2000.
68. Xu X, Weiss ST, Rijcken B, Schouten JP. Smoking, changes in smoking 91. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG.
habits, and rate of decline in FEV1: New insight into gender dier- Association of asthma with serum IgE levels and skin-test reactivity
ences. Eur Respir J 7(6): 105661, 1994. to allergens. N Engl J Med 320(5): 27177, 1989.
69. Strachan DP, Butland BK, Anderson HR. Incidence and prognosis 92. Sears MR, Burrows B, Flannery EM, Herbison GP, Hewitt CJ,
of asthma and wheezing illness from early childhood to age 33 in a Holdaway MD. Relation between airway responsiveness and serum
national British cohort. BMJ 312(7040): 119599, 1996. IgE in children with asthma and in apparently normal children.
70. Kaplan BA, Mascie-Taylor CG. Smoking and asthma among 23-year- N Engl J Med 325(15): 106771, 1991.
olds. J Asthma 34(3): 21926, 1997. 93. Weiss ST. Atopy as a risk factor for chronic obstructive pulmonary
71. Ulrik CS, Frederiksen J. Mortality and markers of risk of asthma death disease. Epidemiological evidence. Am J Respir Crit Care Med 162(3
among 1,075 outpatients with asthma. Chest 108(1): 1015, 1995. Pt 2): S134S136, 2000.
72. Althuis MD, Sexton M, Prybylski D. Cigarette smoking and asthma 94. Hargreave FE, Leigh R. Induced sputum, eosinophilic bronchitis,
symptom severity among adult asthmatics. J Asthma 36(3): 25764, and chronic obstructive pulmonary disease. Am J Respir Crit Care Med
1999. 160(5 Pt 2): S53S57, 1999.
73. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow- 95. Sherrill DL, Lebowitz MD, Halonen M, Barbee RA, Burrows B.
up study of ventilatory function in adults with asthma. N Engl J Med Longitudinal evaluation of the association between pulmonary
339(17): 1194200, 1998. function and total serum IgE. Am J Respir Crit Care Med 152(1):
74. Siroux V, Pin I, Oryszczyn MP, Le Moual N, Kaumann F. 98102, 1995.
Relationships of active smoking to asthma and asthma severity in the 96. Rijcken B, Schouten JP, Weiss ST, Speizer FE, van der Lende R. The
EGEA study. Epidemiological study on the Genetics and Environment association of airways responsiveness to respiratory symptom preva-
of Asthma. Eur Respir J 15(3): 47077, 2000. lence and to pulmonary function in a random population sample. Bull
75. Halken S, Host A, Nilsson L, Taudorf E. Passive smoking as a risk fac- Eur Physiopathol Respir 23(4): 39194, 1987.
tor for development of obstructive respiratory disease and allergic sen- 97. Hospers JJ, Postma DS, Rijcken B, Weiss ST, Schouten JP. Histamine
sitization. Allergy 50(2): 97105, 1995. airway hyper-responsiveness and mortality from chronic obstructive
76. Wartenberg D, Ehrlich R, Lilienfeld D. Environmental tobacco smoke pulmonary disease: A cohort study. Lancet 356(9238): 131317, 2000.
and childhood asthma: Comparing exposure metrics using probability 98. Xu X, Rijcken B, Schouten JP, Weiss ST. Airways responsiveness and
plots. Environ Res 64(2): 12235, 1994. development and remission of chronic respiratory symptoms in adults.
77. Cook DG, Strachan DP. Health eects of passive smoking. 3. Parental Lancet 350(9089): 143134, 1997.
smoking and prevalence of respiratory symptoms and asthma in school 99. Carey VJ, Weiss ST, Tager IB, Leeder SR, Speizer FE. Airways
age children. Thorax 52(12): 108194, 1997. responsiveness, wheeze onset, and recurrent asthma episodes in young
78. Weiss ST, Utell MJ, Samet JM. Environmental tobacco smoke expo- adolescents. The East Boston Childhood Respiratory Disease Cohort.
sure and asthma in adults. Environ Health Perspect 107(Suppl 6): 891 Am J Respir Crit Care Med 153(1): 35661, 1996.
95, 1999. 100. Weiss ST, Tosteson TD, Segal MR, Tager IB, Redline S, Speizer FE.
79. Weil CM, Wade SL, Bauman LJ, Lynn H, Mitchell H, Lavigne J. The Eects of asthma on pulmonary function in children. A longitudinal
relationship between psychosocial factors and asthma morbidity in population-based study. Am Rev Respir Dis 145(1): 5864, 1992.
inner-city children with asthma. Pediatrics 104(6): 127480, 1999. 101. OConnor GT, Sparrow D, Weiss ST. The role of allergy and non-
80. Infante-Rivard C. Childhood asthma and indoor environmental risk specic airway hyperresponsiveness in the pathogenesis of chronic
factors. Am J Epidemiol 137(8): 83444, 1993. obstructive pulmonary disease. Am Rev Respir Dis 140(1): 22552,
81. Infante-Rivard C, Gautrin D, Malo JL, Suissa S. Maternal smoking 1989.
and childhood asthma. Am J Epidemiol 150(5): 52831, 1999. 102. Sluiter HJ, Koeter GH, de Monchy JG, Postma DS, de Vries K, Orie
82. Anthonisen NR, Connett JE, Kiley JP et al. Eects of smoking inter- NG. The Dutch hypothesis (chronic non-specic lung disease) revis-
vention and the use of an inhaled anticholinergic bronchodilator on ited. Eur Respir J 4(4): 47989, 1991.

20
Epidemiology 2
103. Rijcken B, Schouten JP, Xu X, Rosner B, Weiss ST. Airway hyper- 119. Nelson DA, Johnson CC, Divine GW, Strauchman C, Joseph CL,
responsiveness to histamine associated with accelerated decline in Ownby DR. Ethnic dierences in the prevalence of asthma in middle
FEV1. Am J Respir Crit Care Med 151(5): 137782, 1995. class children. Ann Allergy Asthma Immunol 78(1): 2126, 1997.
104. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, 120. Joseph CL, Foxman B, Leickly FE, Peterson E, Ownby D. Prevalence
Wise RA. Methacholine reactivity predicts changes in lung function of possible undiagnosed asthma and associated morbidity among
over time in smokers with early chronic obstructive pulmonary disease. urban schoolchildren. J Pediatr 129(5): 73542, 1996.
The Lung Health Study Research Group. Am J Respir Crit Care Med 121. Weitzman M, Gortmaker SL, Sobol AM, Perrin JM. Recent trends
153(6 Pt 1): 180211, 1996. in the prevalence and severity of childhood asthma. JAMA 268(19):
105. Venn A, Lewis S, Cooper M, Hill J, Britton J. Questionnaire study of 267377, 1992.
eect of sex and age on the prevalence of wheeze and asthma in ado- 122. Carter-Pokras OD, Gergen PJ. Reported asthma among Puerto
lescence. BMJ 316(7149): 194546, 1998. Rican, Mexican-American, and Cuban children, 1982 through 1984.
106. de Marco R, Locatelli F, Sunyer J, Burney P. Dierences in incidence Am J Public Health 83(4): 58082, 1993.
of reported asthma related to age in men and women. A retrospective 123. Hunninghake GM, Weiss ST, Celedon JC. Asthma in Hispanics.
analysis of the data of the European Respiratory Health Survey. Am J Am J Respir Crit Care Med 173(2): 14363, 2006.
Respir Crit Care Med 162(1): 6874, 2000. 124. Thomas SD, Whitman S. Asthma hospitalizations and mortal-
107. Skobelo EM, Spivey WH, St. Clair SS, Schostall JM. The inuence ity in Chicago: An epidemiologic overview. Chest 116(4 Suppl 1):
of age and sex on asthma admissions. JAMA 268(24): 343740, 1992. 135S141S, 1999.
108. Baibergenova A, Thabane L, Akhtar-Danesh N, Levine M, Gafni A, 125. Duran-Tauleria E, Rona RJ. Geographical and socioeconomic varia-
Leeb K. Sex dierences in hospital admissions from emergency depart- tion in the prevalence of asthma symptoms in English and Scottish
ments in asthmatic adults: A population-based study. Ann Allergy children. Thorax 54(6): 47681, 1999.
Asthma Immunol 96(5): 66672, 2006. 126. Mielck A, Reitmeir P, Wjst M. Severity of childhood asthma by soci-
109. Singh AK, Cydulka RK, Stahmer SA, Woodru PG, Camargo CA oeconomic status. Int J Epidemiol 25(2): 38893, 1996.
Jr. Sex dierences among adults presenting to the emergency depart- 127. Strachan DP, Anderson HR, Limb ES, ONeill A, Wells N. A national
ment with acute asthma. Multicenter Asthma Research Collaboration survey of asthma prevalence, severity, and treatment in Great Britain.
Investigators. Arch Intern Med 159(11): 123743, 1999. Arch Dis Child 70(3): 17478, 1994.
110. Melgert BN, Ray A, Hylkema MN, Timens W, Postma DS. Are there 128. Bakke PS, Hanoa R, Gulsvik A. Educational level and obstruc-
reasons why adult asthma is more common in females? Curr Allergy tive lung disease given smoking habits and occupational airborne
Asthma Rep 7(2): 14350, 2007. exposure: A Norwegian community study. Am J Epidemiol 141(11):
111. Prescott E, Bjerg AM, Andersen PK, Lange P, Vestbo J. Gender dif- 108088, 1995.
ference in smoking eects on lung function and risk of hospitalization 129. von Mutius E, Nicolai T, Martinez FD. Prematurity as a risk factor
for COPD: Results from a Danish longitudinal population study. Eur for asthma in preadolescent children. J Pediatr 123(2): 22329, 1993.
Respir J 10(4): 82227, 1997. 130. Haland G, Carlsen KC, Sandvik L et al. Reduced lung function at
112. Mannino DM, Brown C, Giovino GA. Obstructive lung disease birth and the risk of asthma at 10 years of age. N Engl J Med 355(16):
deaths in the United States from 1979 through 1993. An analy- 168289, 2006.
sis using multiple-cause mortality data. Am J Respir Crit Care Med 131. Vergnenegre A, Antonini MT, Bonnaud F, Melloni B, Mignonat G,
156(3 Pt 1): 81418, 1997. Bousquet J. Comparison between late onset and childhood asthma.
113. Gan WQ, Man SF, Postma DS, Camp P, Sin DD. Female smokers Allergol Immunopathol (Madr) 20(5): 19096, 1992.
beyond the perimenopausal period are at increased risk of chronic 132. Jonsson JA, Boe J, Berlin E. The long-term prognosis of childhood
obstructive pulmonary disease: A systematic review and meta-analysis. asthma in a predominantly rural Swedish county. Acta Paediatr Scand
Respir Res 7: 52, 2006. 76(6): 95054, 1987.
114. Martinez FJ, Curtis JL, Sciurba F et al. Gender dierences in severe pul- 133. Kelly WJ, Hudson I, Phelan PD, Pain MC, Olinsky A. Childhood
monary emphysema. Am J Respir Crit Care Med 176(3): 2223, 2007. asthma in adult life: A further study at 28 years of age. BMJ (Clin Res
115. Machado MC, Krishnan JA, Buist SA et al. Sex dierences in survival Ed) 294(6579): 105962, 1987.
of oxygen-dependent patients with chronic obstructive pulmonary 134. Burrows B, Barbee RA, Cline MG, Knudson RJ, Lebowitz MD.
disease. Am J Respir Crit Care Med 174(5): 52429, 2006. Characteristics of asthma among elderly adults in a sample of the
116. Taylor WR, Newacheck PW. Impact of childhood asthma on health. general population. Chest 100(4): 93542, 1991.
Pediatrics 90(5): 65762, 1992. 135. Panhuysen CI, Vonk JM, Koeter GH et al. Adult patients may out-
117. Coultas DB, Gong H Jr., Grad R et al. Respiratory diseases in minor- grow their asthma: A 25-year follow-up study. Am J Respir Crit Care
ities of the United States. Am J Respir Crit Care Med 149(3 Pt 2): Med 155(4): 126772, 1997. [published erratum appears in Am J
S93131, 1994. [published erratum appears in Am J Respir Crit Care Respir Crit Care Med 156(2 Pt 1): 674, August 1997]
Med 150(1):290, July 1994] 136. Ronmark E, Jonsson E, Lundback B. Remission of asthma in the
118. Clark NM, Feldman CH, Evans D, Levison MJ, Wasilewski Y, middle aged and elderly: Report from the Obstructive Lung Disease
Mellins RB. The impact of health education on frequency and cost in Northern Sweden study. Thorax 54(7): 61113, 1999.
of health care use by low income children with asthma. J Allergy Clin 137. Wise RA. Changing smoking patterns and mortality from chronic
Immunol 78(1 Pt 1): 10815, 1986. obstructive pulmonary disease. Prev Med 26(4): 41821, 1997.

21
Natural History
3
CHAPTER

and COPD share common risk factors or, alter-


INTRODUCTION natively, by the possible progression of persistent Stefano Guerra and
asthma into chronic airow limitation, the clini- Fernando D. Martinez
There is increasing interest in developing a better cal hallmark of COPD [4]. It is often not pos-
Arizona Respiratory Center and Mel
understanding of the natural history of the two sible to determine whether persons with airow
limitation have asthma or COPD. However, and Enid Zuckerman College of Public
most frequent chronic lower respiratory diseases,
understanding the natural history of the disease Health, University of Arizona, Tucson,
asthma and chronic obstructive pulmonary dis-
ease (COPD). The main reason for this interest is will have critical implications for identifying AZ, USA
the shift in the therapeutic approach to both con- optimal prevention and treatment strategies.
ditions. In the case of asthma, a growing body of
evidence suggests that, although several current
treatments for the disease are extremely eec-
tive in controlling symptoms, none can change
METHODOLOGICAL APPROACH
its natural course. It is thus evident that new
approaches to the primary and secondary pre- Any discussion about the natural history of a
vention of asthma are needed. These approaches chronic condition ought to address the dierent
will require a thorough understanding of the fac- hypothetical phases that such condition under-
tors that determine the inception of asthma and goes during its lifetime course (Fig. 3.1).
its progression with age. In the case of COPD, There is rst a pre-illness period during
it is apparent that, although smoking is the main which subjects without overt disease have the sus-
demonstrated cause of this condition, a simple ceptibility for the development of the condition,
strategy of discouraging tobacco consumption because of a genetic predisposition or because
has proven insucient to prevent the enormous of injuries or developmental variations that have
impact of nicotine addiction on public health. mutated one or more of the individuals disease-
A new understanding of the factors that increase associated phenotypes. During this pre-illness
the risk of COPD in smokers seems a more real- phase, the susceptible individual is not yet des-
istic approach, and could perhaps contribute to tined to develop the disease. More likely, he or
palliate the increasing social toll of COPD. she may be exposed to environmental factors that,
When discussing the natural history of in the presence of genetic variants that predispose
asthma and COPD, an important issue is the to the chronic condition, can further modify their
overlap between these two conditions [1]. It has phenotype. This model applies to both asthma
been conclusively shown that, at the population and COPD, as they are both likely to represent
level, adults who report asthma are more likely to heterogeneous diseases with multiple ways to
also report chronic bronchitis and/or emphysema reach nal common pathways and an array of
as compared with subjects with no asthma [2] diverse pathogenetic mechanisms giving rise to
and recent epidemiological evidence shows that more or less reversible airway obstruction.
active asthma is a strong risk factor for acquir- It would obviously be of great help for any
ing a subsequent diagnosis of COPD [3]. This prevention strategy if markers of susceptibility
overlap may be explained by the fact that asthma were identied that could be measured during

23
Asthma and COPD: Basic Mechanisms and Clinical Management

Inception Transient early Nonatopic IgE-associated


n Chronic
wheezers wheezers wheeze/asthma
sio disease
es
ogr
Pr

Wheezing prevalence
Protection Intermittent
No disease Initial phase
disease

Re
mi
ss
ion
Triggers No disease

FIG. 3.1 Hypothetical representation of the natural history of a chronic


condition. For explanation see text.

this pre-illness phase. But the absence of a marker in a spe- 0 3 6 11


cic individual may not exclude susceptibility if that is not the Age (years)
pathway that may be active in that individual. Thus, because
FIG. 3.2 Hypothetical yearly peak prevalence of wheezing for three
the marker phenotype may be inuenced by determinants
different phenotypes in childhood. Prevalence for each age interval should
other than the factors that inuence asthma or COPD risk, be the sum of the areas under each curve. The dashed curves suggest
ascertainment of a marker may be fraught with diculties. wheezing can present different curve shapes due to many different factors,
This context-dependency [5] of the phenotypes of markers including overlap of groups. Adapted from Ref. [15].
of disease creates a further layer of complexity for the identi-
cation of susceptible individuals.
The above discussion points to the importance of
manifestations of asthma occur during the rst 5 years of
determining the true time of incidence of the disease under
life [6, 11, 13]. Studies have ascertained this age of onset of
study. Although the event that is easiest to ascertain is the age
symptoms either by asking parents about the prevalence of
of initiation of symptoms, this event is modied by patients
wheezing or other asthma-like symptoms in their children
perceptions. What is important is that time of onset ought
at dierent ages, or by reviewing previous clinical charts in
to be ascertained before the disease has become chronic, that
subjects who present to outpatient clinics with signs and
is before the individual has evidence of physiological or ana-
symptoms of asthma at any age. Although these studies
tomical changes caused by the disease itself and that predis-
strongly suggest that asthma started at an early age in these
pose to persistent or recurrent symptoms. During this initial
individuals, a simple connection between these two phe-
phase of the disease, the aected individual has some clinical
nomena is not warranted. Many children have asthma-like
manifestations, but the condition has not yet fully developed.
symptoms during viral infections in their preschool years,
Moreover, some individuals may not go beyond this initial
but most have transient conditions that subside with age,
phase, because remission or stabilization may be fostered by
and only a minority will go on to have persistent asthma
the presence of environmental or genetic protective factors.
[14]. Thus it is dicult to distinguish who will go on to
During this initial phase secondary prevention is possible,
develop chronic asthma from those who will not.
but again knowledge of the natural history becomes essential.
Studies of this issue have suggested that there are at
least three quite distinct groups of children with asthma-like
symptoms coexisting up to the adolescent years (Fig. 3.2).
NATURAL HISTORY OF ASTHMA PHENOTYPES The great majority of infants who wheeze during the rst
12 years of life do so during viral infections, especially
those caused by the respiratory syncytial virus (RSV) and
Asthma is a heterogeneous condition, and one of the main by rhinovirus. Most of these children will have one or only
obstacles in understanding its natural history has been a few episodes of wheezing, with no further symptoms
the lack of well-dened markers for the dierent disease beyond the age of 23 years. This condition, which has been
phenotypes grouped under this common label. This hurdle identied as transient wheezing of infancy [16], is the most
has been addressed lately by a series of longitudinal studies frequent form of recurrent airway obstruction in this age
that have assessed incidence and prevalence of asthma group, aecting over two-thirds of all infants with asthma-
at dierent ages or dened the outcome of persons with like symptoms. The main predisposing factors for transient
asthma-like symptoms enrolled at dierent ages and espe- wheezing of infancy are maternal smoking during preg-
cially during childhood [613]. nancy and lower levels of lung function, as assessed during
the very rst months of life and before any wheezing epi-
sode has occurred. Interestingly, infants (especially females)
Most cases of chronic, persistent asthma whose mothers smoke during pregnancy do have lower
start in early life levels of lung function early in life than those whose moth-
ers do not smoke [17]. This has suggested the possibility
Several longitudinal studies have conrmed that, in most that both inherited and acquired characteristics of the lung,
cases of chronic, persistent asthma, the initial clinical the airways, or both may create the structural conditions for

24
Natural History 3
the development of airway obstruction during lower respi- 40
ratory illnesses [18]. Alternaria negative asthma
The factors that determine the remission of early life Alternaria positive asthma
wheezing in these children are not well understood, but
it is likely that growth of the airways may outpace that of 30

Percentage of asthma group


the lung parenchyma after age 25 months, the period of
the highest incidence of wheezing episodes [19]. Since the
airways are growing faster than the parenchyma, the condi-
tions required for airow to be dynamically obstructed may
not be easily reached and noisy breathing is less likely [19]. 20
It is also possible that changes in the regulation of airway
tone may result in decreased bronchial hyperresponsiveness
and decreased likelihood of respiratory symptoms with age
[20, 21]. However, despite remission of wheezing with age 10
in this group, children with early transient wheezing appear
to have lower levels of lung function, in terms of FEF2575,
FEV1, and FEV1/FVC ratio values, throughout childhood
as compared with their peers who did not wheeze in the 0
rst 6 years of life [22]. It is established that individuals 0
01 12 23 34 45 56 67
who enter adulthood with lung function decits are more Age at which asthma diagnosed (years)
likely to develop COPD during the late adult years, sug-
gesting that children with early transient wheezing may be FIG. 3.3 Age of diagnosis of asthma for children who are skin-test positive
particularly predisposed to COPD in adult life if exposed for Alternaria or skin-test negative for Alternaria at age 6 in the Tucson
to cigarette smoking. Whether this is the case is at present Childrens Respiratory Study. Adapted from Ref. [24].
unknown.
The factors that determine enduring or newly devel-
oped abnormalities in lung function during the rst years with a history of RSV-LRI than in those with no such
of life are the subject of intense scrutiny, because they seem history. However, the risk decreased with age and was not
to be clearly associated with the risk of persistent asthma. statistically signicant by early adolescence. There was also
Zeiger et al. [23] showed an inverse relationship between no association between RSV-LRI and subsequent risk of
duration of symptoms and level of lung function in school- sensitization to local aeroallergens either at age 6 or at age
age children with asthma, and this suggests that the ear- 11 years. The only factor that was strongly associated with
lier onset of asthma symptoms is associated with greater RSV-LRI in early life was diminished baseline levels of
losses in lung function. Sensitization to local aeroaller- FEV1, as measured at age 11. Interestingly, these decits
gens is strongly associated with increased risk of chronic were reversed by use of a bronchodilator, suggesting that
asthma-like symptoms into adult life. Using this knowledge, they were likely to be due to increased bronchomotor tone.
Halonen et al. [24] divided children who had a diagnosis of Longitudinal studies performed in the early 1980s had also
asthma by age 6 years into two main groups: those who at suggested that the outcome of RSV-LRIs is usually benign
age 6 were skin-test positive for Alternaria, the main aeroal- and unrelated to increased allergic sensitization [26].
lergen associated with asthma in the study area [25], and It thus appears that at least three dierent forms of
those who were not. They observed that, in the majority of asthma coexist during infancy and early childhood (Fig. 3.2).
children in both groups, symptoms had started before age Transient infant wheezing is quite frequent, is usually trig-
3 years. However, among children with asthma who were gered by viruses (especially RSV), and, although it is con-
skin-test negative to Alternaria, inception of the disease had ned to the rst 3 years of life, may be associated with
occurred mainly during the rst year of life; while in those long-term lung function decits. Other children who
who were skin-test positive to Alternaria, peak incidence wheeze during viral infections in early life continue to have
occurred during the second and third years of life (Fig. 3.3). recurrent respiratory symptoms during the early school
The fact that young children who will go on to years. This form of nonatopic wheezing is associated with
develop chronic, atopy-related asthma by age 6 are diag- lower levels of lung function during the school years, but
nosed 1 or 2 years later than those with nonatopic asthma these lower levels seem to be reversible after use of a bron-
suggests that the mechanisms of disease are likely to be chodilator. Finally, children who will develop atopy-related
dierent in these two groups. Support for this contention asthma start having symptoms mainly during the second
comes from a slightly dierent analysis of the data from and third years of life.
the same cohort on which Halonen and coworkers based
their report quoted above. Stein et al. [14] assessed the out-
come of children with conrmed lower respiratory tract ill- Chronic asthma is most often related
nesses due to RSV (RSV-LRI), after adjusting for all other to atopy
known risk factors for subsequent asthma, including skin
test reactivity, maternal history of asthma and birth weight, There is now strong evidence indicating that, as a group,
among others. They found that, as previously reported, risk individuals with chronic asthma at any age between the ele-
of wheezing during the school years was higher in children mentary school years and mid-adult life are either sensitized

25
Asthma and COPD: Basic Mechanisms and Clinical Management

to local aeroallergens, have elevated total levels of circulat- the immune system and, in turn, they may lead to susceptibil-
ing IgE, or both [27]. Although the association between ity to viral infections, favor a Th2 skewed polarization of the
asthma and total and specic IgE is well established, the immune system, and aect airway growth. Whether decits
nature of the association is not well understood. For years of early IFN responses can explain the link between asthma
it was thought that sensitization to specic allergens, espe- and atopy or simply represent one of multiple pathways that
cially in early life, was a cause of asthma [28], and that are shared by these two phenotypes remains unknown.
development of specic IgE against these allergens was the
rst step in the natural history of the disease. The strong
association between risk of having asthma and sensitiza- Outcome of childhood asthma in adolescence
tion to the allergens of house dust mites in coastal regions
seemed to argue in favor of this hypothesis, and strategies and adult life: Remission of mild asthma and
for the primary prevention of asthma based on avoidance persistence of severe disease
of exposure to these allergens were proposed [29]. However,
several studies performed in desert areas with low exposure Only a few population-based studies have addressed the
to house dust mites showed that the prevalence of asthma outcome of childhood asthma in adolescence and adult life.
was either similar or even higher in these regions than These studies have used longitudinal assessment of asthma
that observed in zones where mite infestation rates were symptoms and lung function in children who were enrolled
high [25, 30]. In desert regions, the allergens of the mold at birth [12] or during the early school years [36, 37] or
Alternaria appeared to be strongly associated with asthma. who were part of birth cohorts for which assessment of
Moreover, studies in northern Sweden, where indoor expo- asthma symptoms in early life was made through retrospec-
sure to either dust mites or molds is very low, showed that tive questionnaires [7, 8, 10, 38].
the prevalence of school-age asthma is very similar to that The transition of asthma from childhood into adoles-
observed in southern Sweden, where exposure to house dust cence has been studied in the birth cohort of the Tucson
mites is high [31]. Interestingly, only 50% of all schoolchil- Childrens Respiratory Study [12]. In that study, most
dren with asthma are sensitive to known aeroallergens in children who experienced only infrequent wheezing dur-
northern Sweden (especially cat and dog), compared with ing childhood had remission of wheezing after puberty.
over 90% of children in more temperate regions, but skin- However, almost 60% of children with frequent wheezing
test negative children with asthma have signicantly higher and/or a physician-conrmed diagnosis of asthma expe-
IgE levels than nonasthmatic children [31]. These obser- rienced wheezing at some point during adolescence. These
vations suggest that, regardless of the nature of the asso- results challenge the commonly held view that most chil-
ciation between elevated IgE and asthma, this link is not dren with asthma outgrow the disease in adolescence and
allergen-specic. suggest that complete remission of the disease may be the
Recent epidemiological studies have challenged the exception rather than the rule, at least among cases of mod-
view of a unidirectional link between atopy and asthma. erate to severe asthma.
Our group found that parental asthma is a strong predictor This link between severity and persistence of asthma
not only for asthma in the child (as one would expect), but has been conrmed by long-term prospective studies that
also for the childs total IgE levels and skin test reactivity have followed cohorts of children into mid-adult life. The
[32]. These relationships remained signicant after adjusting longest such ongoing study is that initiated by Williams and
for the intensity and other characteristics of parental atopy, McNicol in Melbourne, Australia [39]. Children with a his-
supporting independent eects of parental asthma on the tory of recurrent episodes of wheezing were enrolled at the
development of atopy in the child. Previous studies had also age of 7 years, together with a small group of controls with-
shown that, although the level of allergen exposure early in out such a history. These individuals were then periodically
life predicts the development of allergic sensitization and reassessed, and the latest published data refer to information
allergic sensitization is associated with subsequent develop- collected when their mean age was 42 years. Information
ment of asthma, no direct link between allergen exposure about the age upon initiation of symptoms was obtained
early in life and subsequent development of asthma could by use of questionnaires and, as a consequence, data on a
be demonstrated. crucial period of life for the development of asthma was
All these studies suggest that the essential causal possibly biased by preferential recall [36, 40]. The sec-
mechanism associated with asthma is not sensitization to ond study was the British 1958 birth cohort, in which
any specic allergen, but more likely is an alteration in the over 18,000 subjects born between March 3 and March 9,
regulation of responses to many dierent antigens with 1958 were enrolled [8]. Of these persons, 31% contributed
the potential of eliciting IgE responses, and especially to information for ages 7, 11, 16, 23, and 33 years. As with
aeroallergens. IFN production might be among these the Melbourne study, information for the rst 7 years of
altered immunological responses. In the Tucson cohorts of life was obtained retrospectively at age 7. Similarly, in the
the Childrens Respiratory Study [33, 34] and the Infant Dunedin Multidisciplinary Health and Development Study
Immune Study [35], our group found strong associations (New Zealand) parents completed rst respiratory ques-
between reduced IFN production from polyclonally stimu- tionnaires when children were already 9 years old. To date,
lated peripheral blood mononuclear cells in the rst year of participants have been followed up to age 26 with repeated
life and the subsequent development of both allergic sensi- questionnaires and lung function measurements [7]. Finally,
tization and asthma-related respiratory symptoms. Reduced the Tasmanian asthma survey enrolled over 8000 chil-
IFN responses may be related to a delayed maturation of dren born in 1961 who were also rst contacted at age 7

26
Natural History 3
[10]. Two thousand randomly chosen individuals were lung function as measured in early school age was a sig-
re-examined when they were 2932 years of age. nicant predictor of subsequent persistent wheezing. In the
The most important ndings of all four studies were Melbourne study, lung function for each subgroup of sub-
that asthma remits, at least transiently, in early adulthood jects classied according to their wheezing history by age 7
in a sizable proportion of asthmatic children, and that the was repeatedly assessed up to the age of 42 years. Children
severity of asthma tracks signicantly with age. This second with severe asthma at age 10 had very low initial levels of
point is important because it reects a stability in the dis- lung function, and this was to be expected because decits
ease: most children with severe symptoms still have severe in lung function were used to classify them as having severe
symptoms as adults, and asthmatic children with mild symp- asthma in the rst place. When compared with their peers,
toms either have no asthma or have mild asthma as adults. these children did not show further decits in lung func-
tion growth with age, and by age 42 their position relative
Children enrolled in the Melbourne study were divided to subjects with milder symptoms or with no asthma was
at the time of enrollment into ve groups according to substantially unchanged. A similar pattern of relatively sta-
their previous history of wheezing: a control group (no ble lung function growth was observed for patients with
wheezing), a group with mild wheezy bronchitis (less mild asthma who had shown loss of lung function at enroll-
than ve lifetime episodes of wheezing associated with ment, albeit much less pronounced than persons with severe
colds), a group with wheezy bronchitis (ve or more such asthma. Similarly, in the Dunedin study children with per-
episodes), a group with asthma (wheezing apart from sistent wheezing had consistently lower values of the FEV1/
colds), and a group with severe asthma (selected at age FVC ratio from age 9 up to age 26, as compared with con-
10 based on severe impairment of lung function). At age trols. The mean decit was almost 7%, but no signicant
42 years, less than a quarter of children with either form dierences in the slopes of change in the FEV1/FVC ratio
of wheezy bronchitis showed frequent asthma episodes were found between persistent wheezers and controls. Thus,
(wheezing during the previous 3 months, but less than persistent wheezers had decreased values of FEV1/FVC, but
once a week) or persistent asthma (once a week or more). not steeper slopes of decline. These ndings are very rele-
However, 52% of children with asthma and 76% of vant for our understanding of the natural history of COPD,
those with severe asthma at the time of enrollment had and will be discussed in more detail below.
frequent or persistent wheeze at age 42 [40]. The potential role of bronchial hyperresponsiveness in
Similar results have been reported based on the British school age has been explored in two of the above referenced
1958 study: 27% of all children whose parents reported cohorts. In the Dunedin study, the presence at 9 years of
they had wheezed before age 7 reported wheezing during age of either a value of methacholine PC20  8 mg/ml or
the previous year at age 33 [8]. an increase of FEV1  10% from baseline in response to a
bronchodilator was associated with fourfold increased odds
In the Dunedin study, 37% of children who ever for persistent wheezing and with almost sevenfold increased
wheezed had wheezing that persisted from childhood to odds for relapse of wheezing [7]. In that study, bronchial
adulthood or that relapsed after remission [7]. hyperresponsiveness remained signicantly associated with
For the Tasmanian study, 25.6% of subjects with asthma both outcomes after adjusting for other risk factors. In the
or wheezy breathing by age 7 reported current asthma Tucson Childrens Respiratory Study, we found 68% of the
at the age of 2932 years, compared with only 10.8% of children whose asthma persisted after the onset of puberty
subjects without parental reports of childhood asthma to have had a positive test for bronchial hyperresponsiveness
[10]. As with the Melbourne study, those who had a at age 11, as compared with only 37% of children whose
history of more than 10 attacks of asthma by age 7 were asthma remitted during adolescence [12]. Another interest-
almost twice as likely to have persistent wheezing as ing nding of that study was the strong association between
adults than those who did not. childhood obesity and persistence of asthma after the onset
of puberty. Multiple recent reports have consistently linked
A consistent factor associated with persistent asthma obesity not only to persistence but also to incidence of
in all four cohorts was evidence of an allergic predisposition. asthma [4144]. The nature of this association remains at
In the Melbourne study, severe asthma in early life was present not fully understood and warrants further research.
associated with signicantly higher prevalence of allergic
rhinitis at age 35. In the British cohort, allergic symptoms
(e.g. allergic rhinitis or eczema) were signicantly associ- Relapse of asthma symptoms in patients
ated with persistence of symptoms into adult life. In the whose asthma remitted in childhood
Dunedin cohort, skin sensitization to house dust mites
increased more than twice the odds for both persistence and Little is known about prevalence and risk factors for relapses
relapse of wheezing, independent of other predisposing fac- of asthma in adult life among subjects whose symptoms
tors [7]. Finally, in the Tasmanian cohort, having a history remitted during childhood. Taylor and colleagues found
of eczema in early life was also signicantly associated with one-third of subjects who had childhood asthma that was in
persistent wheezing at ages 2932. remission at age 18 to have relapses of the disease in young
Childhood decits in lung function are another fac- adulthood [45]. In the British cohort study, a group of over
tor that has been consistently associated with persistence 1300 persons with a history of wheezing illnesses from
of asthma into adult life across dierent cohorts. In the birth to age 16 years had symptom remission by age 23. This
Tasmanian, the Melbourne, and the Dunedin studies, low group was 50% more likely to report wheezing at age 33

27
Asthma and COPD: Basic Mechanisms and Clinical Management

than those with no history of asthma or wheezy bronchitis 100

FEV1 (% normal level at age 20)


during childhood [8]. These ndings suggest that complete (c)
remission of asthma in adulthood may be less common (a)
80 (d)
than previously thought and are consistent with results
from clinical studies supporting the presence of active,
subclinical forms of the disease among asthmatics in clini- 60
cal remission. In a Dutch cohort of 119 patients who were (b)
diagnosed with asthma during school age and re-examined 40
30 years later (at age 3242), bronchial hyperresponsiveness
and/or reduced lung function were present among 57% of 20
those who were in clinical remission as adults [46]. Previous
studies have shown that indicators of airway inammation,
such as eosinophils and IL-5 in bronchial biopsies, eosi- 0
0 10 20 30 40 50 60 70 80
nophil percent in bronchoalveolar lavage, and exhaled nitric Age (years)
oxide levels, are higher among children and adolescents in
clinical remission of asthma, as compared with their peer FIG. 3.4 Hypothetical mechanisms that may lead to a critically low level
controls [4749]. Bronchial hyperresponsiveness and other of lung function in adult life and to chronic airway obstruction (horizontal
clinical abnormalities among these apparently remitting line): (a) normal growth and decline; (b) impaired lung growth with a lower
asthma cases may pose these subjects at increased risk for plateau phase but a normal rate of decline compared to (a); (c) normal
obstructive lung disease in adult life and their potential role plateau with rapid initial decline in lung function and a subsequent normal
as determinants of COPD will be discussed below. rate of decline; (d) normal plateau with normal initial rate of decline but a
subsequent accelerated loss in lung function. Adapted from Ref. [51].

NATURAL HISTORY OF COPD of lung function at the beginning of adult life as in individ-
uals who already have a diminished level of lung function to
begin with.
According to the Global Initiative for Chronic Obstructive The essential determinants of the natural history of
Lung Disease (GOLD) [50], the pulmonary component COPD are the rate of growth of lung function up to late
of COPD is characterized by airow limitation that is not childhood, the timing and length of the plateau phase, and
fully reversible, usually progressive, and associated with the rate of decline of lung function during adult life.
an abnormal inammatory response of the lung to nox-
ious particles or gases. Thus, the natural history of COPD
overlaps extensively with that of the level of lung function
(usually FEV1, expressed as percent of predicted value in Growth of lung function during childhood
relation to a certain height) during adulthood. Three are the
main factors that can determine the level of lung function The three most important determinants of growth of lung
achieved at any age during adult life (Fig. 3.4). function during childhood are:
First, the individual may either start life with a low level the level of lung function at birth,
of lung function or show a signicant decline in lung func-
tion growth during the rst years of life (line b in Fig. 3.4). the incidence of lower respiratory illnesses during the
The individuals level of lung function will fall after a certain rst years of life,
age, at the same rate as normal peers, but at a lower level the development of persistent asthma-like symptoms
overall. The level of lung function attained by late adoles- during childhood.
cence or early adult life will thus be lower. Through the nor-
mal process of aging, decline in lung function will naturally
occur, and this decline, although parallel to that occurring Level of lung function at birth
in all the population, will nevertheless predispose to the The availability of lung function tests that can be performed
attainment of a level of lung function (expressed as percent- shortly after birth, and which appear to show good correlation
age of normal level in early adulthood) that will be lower with more invasive tests of airway function [52], has allowed
than the threshold for the expression of clinical symptoms us to study the potential role of the development of the lung
of airway obstruction. in utero on subsequent levels of lung and airway function
A second potential mechanism is that of an early attained by the individual. Since these methods have been
decline in lung function occurring either at the end of ado- available only for the last 25 years, it is not possible to deter-
lescence or in early adult life (line c in Fig. 3.4). Again, the mine the role of airway function in the postnatal period on
main result of such a mechanism would be the attainment events occurring beyond young adult life. Nevertheless, it is
of lower level of lung function in these individuals as com- now apparent that there is quite signicant tracking between
pared with the rest of the population. the level of lung function measured shortly after birth and
A third mechanism is that of a faster rate of decline that measured during childhood [53, 54], adolescence [22],
of lung function during adult life (line d in Fig. 3.4). This and up to young adulthood [55]. This may explain, at least in
may obviously occur both in individuals with a normal level part, the strong association between lower respiratory illness

28
Natural History 3
in early life and level of lung function in late childhood and of lung function [63]. This hypothesis seemed attractive,
early adulthood (see the discussion below). because it suggested a potential strategy for the prevention
The factors that determine growth of lung and air- of early losses in lung function that could predispose to
ways in utero are only partly understood. The two main COPD. However, several studies in which the techniques
determinants of the level of lung function measured shortly to assess lung function in infants, described earlier, were
after birth are gender and exposure to tobacco smoke prod- used showed that children who developed lower respira-
ucts in utero [56]. Boys have been found to have consist- tory symptoms during viral infections in early life had
ently lower maximal ows at functional residual capacity diminished pre-illness levels of lung function [18, 56, 59].
(VmaxFRC) throughout the rst year of life in comparison The hypothesis was thus suggested that lower levels of lung
with girls. Indeed, females have larger airway size, rela- function observed after lower respiratory illnesses in early
tive to the size of lungs and to body size, as compared with life could be explained by preexisting diminished lung func-
males both at birth and during childhood, up to the plateau tion, the latter being therefore the link between early life
of lung growth [57]. However, the role of these gender dif- episodes of airway obstruction and subsequent decits in
ferences in inuencing airway function and predisposing to lung function.
obstructive lung disease is not well understood. Maternal Unfortunately, the number of infants in whom lung
smoking during pregnancy is associated with lower levels function has been ascertained in early life and who have
of VmaxFRC in both genders in comparison with unexposed been followed for a number of years after birth is rather
infants [56]. Postnatal exposure to tobacco smoke appears small. Therefore, the possibility that lower respiratory ill-
to be less important than prenatal exposure, at least in most nesses by themselves may alter lung and airway growth in
developed countries [58]. The eects of intrauterine expo- groups of susceptible individuals cannot be excluded. It is
sure to tobacco smoke products persist for the rst year unlikely that pre-illness lung function may explain all forms
of life [56], and even beyond the rst year up to the early of infection-associated wheezing during early childhood,
adolescent years [59]. and it is legitimate to surmise that immune responses to the
Independent of what factors determine in utero lung viruses themselves may also play a signicant role.
growth, evidence has been accumulating that lung func- Evidence from studies in the United Kingdom would
tion at birth aects lung health far beyond infancy. In addi- support the validity of both hypotheses [6466]. In a cohort
tion to the well-established association between reduced of children enrolled in 1964 and reassessed in 2001 for cur-
VmaxFRC shortly after birth and wheezing in the rst years rent lung function, smoking status, and respiratory symp-
of life [18, 56, 59, 60], recent studies have associated lung toms, a signicant linear trend was found between birth
function measured in the rst month of life to persistent weight and FEV1 at age 4550 years after adjusting for
wheezing and asthma at 1011 years [54, 61]. Turner et al. confounders, including smoking [65]. This association was
found wheezing at 11 years to be associated with a reduced conrmed by a recent meta-analysis [66] of eight stud-
mean z score for VmaxFRC at 1 month of age [54], whereas a ies reporting a pooled increase of 48 ml in FEV1 per 1 kg
reduced fraction of expiratory time to peak tidal expiratory in birth weight. As modest as this association may appear,
ow to total expiratory time (tPTEF/tE) as assessed 3 days these ndings support a direct inuence of in utero growth
after birth predicted asthma and bronchial hyperrespon- on lung function in adulthood. However, another very long-
siveness at age 10 years in a Norwegian birth cohort [61]. term study in England provides evidence in support of addi-
Of note, in the latter study tPTEF/tE at birth did not cor- tional eects of childhood respiratory infections on adult
relate with FEV1 or FVC at 10 years of age. These ndings lung function [64]. In this study, men born between 1911
are complemented by results from the Tucson Childrens and 1930, whose birth weights, weights at 1 year, and child-
Respiratory Study, in which we found VmaxFRC measured hood respiratory illnesses were recorded in early life, were
at 2 month of age to correlate strongly with FEV1 and the studied at ages 5970 years. Death from chronic obstruc-
FEV1/FVC ratio assessed at age 11, 16, and 22 years [55]. tive disease, FEV1, and respiratory symptoms were the main
Participants in the lowest quartile for infant VmaxFRC had outcome variables. The main early life determinants of the
a 5% mean decit in the FEV1/FVC ratio through age 22 level of FEV1 in old age were birth weight and history of
compared to the upper three quartiles and this association bronchitis or pneumonia in infancy, and these eects were
was independent of wheezing and asthma status. Taken independent of smoking habit and social class. These data
together, this evidence suggests that lung function at birth would thus suggest that both intrauterine growth (and
accounts for part of the lung function levels attained in presumably lung development) and lower respiratory ill-
young adult life and, in turn, may inuence predisposition nesses during the rst years of life exert independent eects
to subsequent obstructive lung disease. on the level of lung function attained late during adult
life, and thus may be important determinants of the risk
of COPD.
Role of lower respiratory illnesses in early life
It has been known for decades that children who have
lower respiratory illnesses during the rst years of life have Persistent asthma-like symptoms during
lower levels of lung function during childhood and into childhood
adult life [62]. One possible explanation for this association Epidemiological evidence supports that persistent asthma-
is that viral infections, which are the main etiological fac- like symptoms are a signicant risk factor for the devel-
tor for lower respiratory illnesses in early life, may damage opment of lower levels of lung function in childhood and
lung and airways, and this may predispose for lower levels young adult life [7, 36] and, in turn, may predispose to the

29
Asthma and COPD: Basic Mechanisms and Clinical Management

development of COPD. One proposed explanation for of lung function is reached in early adult life. Xuan et al.
these associations has been that asthma is a progressive [72] observed that, between the ages of 17 and 19 years,
disease [67]. It has thus been proposed that the presence of when growth in height had stopped, FEV1 continued to
chronic airway inammation is associated with signicant grow in both males and females. However, children who
lung remodeling and that the latter fosters a signicant had recent episodes of wheeze and those with evidence of
alteration in lung growth. bronchial hyperresponsiveness showed a reduced rate of
Although some studies were able to show impair- growth in airway caliber. Unfortunately, lung function was
ment in the development of lung function in children not assessed after use of a bronchodilator, and it is thus not
with asthma [67, 68], the main outcome variable used in possible from these data to assess whether the changes are
these studies was pre-bronchodilator lung function. The due to increased airway tone or to irreversible alterations
Childhood Asthma Management Program (CAMP) study in airway structure. In addition to active wheezing and
was specically designed to test the hypothesis that mild to bronchial hyperresponsiveness, early initiation to cigarette
moderate childhood asthma is associated with signicant smoking has been associated with detrimental eects on the
deterioration in airway growth and that treatment with plateau level of lung function. Holberg et al. [73] showed
inhaled anti-inammatory therapy could reverse this dete- that, at age 16, the level of lung function achieved by males
rioration in lung function [69]. Children aged 612 years who had started smoking was signicantly lower than
were treated for 46 years with either an inhaled corticos- that of those who had not. No such eect was observed in
teroid (budesonide), nedocromil, or a placebo. Post-bron- females.
chodilator FEV1 was considered the outcome variable,
because pre-bronchodilator FEV1 could be aected by the
degree of activity of the disease at the time of testing. The Determinants of increased slope of lung
results of the study showed that, although children with function decline
asthma have levels of lung function that are signicantly
lower than those of children without the disease at any time Several longitudinal studies have addressed the role of dif-
between the ages of 6 and 15, these levels do not further ferent intrinsic and extrinsic factors on the rate of decline
deteriorate even among subjects who are not systematically of lung function after the plateau phase. The role of ciga-
treated with anti-inammatory therapy. Moreover, system- rette smoking has been clearly and consistently established.
atic treatment with anti-inammatory therapy improves Camilli et al. [74] examined changes in FEV1 in over 1700
bronchial hyperresponsiveness, but is not associated with a adults enrolled in a prospective study of a general popula-
signicant improvement in lung function with time. Based tion sample. Individuals who smoked more than 10 ciga-
on these ndings, more recently the Prevention of Early rettes per day had excessive rates of decline in FEV1 as
Asthma in Kids (PEAK) trial was designed to determine compared with nonsmokers. The excess decline of smokers
whether the lack of sustained eects of inhaled corticoster- was age dependent, particularly in men: much of the excess
oids on the natural history of childhood asthma was attrib- loss of lung function occurred between 50 and 70 years of
utable to the initiation of the intervention too late in life. In age. Interestingly, ex-smokers showed declines in FEV1 val-
fact, the PEAK trial failed to detect any long-term eects ues that were similar to those of nonsmokers. The authors
of a 2-year treatment with inhaled corticosteroids on the also examined the eect of quitting smoking on the decline
natural history of asthma in a group of high-risk preschool of FEV1. In subjects younger than 35 years, quitting smok-
children, despite the temporary benecial eects of the ing during follow-up was associated with an actual increase
treatment on disease symptoms and exacerbations [70]. in FEV1. In men above 50 years, smoking cessation early in
An interpretation of these results is that, in chil- the study led to a return to normal rate of functional decline
dren with a diagnosis of asthma, most of the deterioration during follow-up. In addition to cigarette smoking, exposure
in lung function observed during the school years occurs to other toxic gases and particles including environmental
early in life. The results of studies by our group suggest that tobacco smoke, indoor and outdoor pollution, occupational
children who go on to have persistent asthma-like symp- dust, gases, and fumes has been consistently associated
toms during childhood start life with levels of lung func- with COPD and a steeper decline of lung function [75, 76].
tion that are slightly lower than those of children who will However, the observation that only a more [77] or less
not have these persistent symptoms [71]. It is also possi- [78] sizable fraction of smokers develop COPD strongly
ble that persistent childhood asthma aects lung function suggests the existence of intrinsic factors that can modify
through mechanisms that are at least partly unrelated to the eect of smoking and other deleterious exposures on
airway inammation and, therefore, insensitive to corticos- the rate of decline of lung function. Bronchial hyperre-
teroid treatment. Finding the answer to these questions will sponsiveness has been long hypothesized to be one of these
have crucial implications for the prevention of long-term factors [79, 80]. Indeed, bronchial hyperresponsiveness has
obstructive lung disease among these children. been consistently shown to be a strong and independent
risk factor for accelerated decline of lung function in pro-
spective studies among smokers with early COPD as well
Determinants of early losses in lung as asymptomatic individuals [8183]. Findings from these
function epidemiological studies have been conrmed in the clinical
setting. For instance, Postma and coworkers [84] assessed
Very little is known about the factors that determine early the course of lung function after 221 years of follow-up
losses in lung function at the age in which the plateau level in 81 nonallergic patients with considerable lung function

30
Natural History 3
impairment (55% FEV1/FVC ratio) at the beginning of
the study. They reported that a more favorable rate of change INTERSECTION OF THE NATURAL HISTORY OF
in FEV1 was not only associated with fewer pack-years of ASTHMA AND COPD
smoking but also with less nonspecic bronchial hyperreac-
tivity and a higher degree of reversibility of airow obstruc- It is not uncommon in the clinical setting to observe
tion. These eects were independent of baseline FEV1 value, patients with asthma showing COPD-like phenotypes,
both in smokers and in ex-smokers. Whether the association and vice versa. Consistently, it has been long known that
between bronchial hyperresponsiveness and decline in lung diagnoses of asthma, chronic bronchitis, and emphysema
function is the consequence of an ongoing COPD-related are frequently associated at the population level [2]. This
inammatory process and to what extent this inammatory evidence indicates that the natural history of asthma and
process diers from that associated with bronchial hyperre- COPD can converge in some cases during adult life. A pos-
sponsiveness in asthma remain at present open questions. sible explanation for these observations is that a signicant
Airway inammation and its structural sequelae may proportion of cases with severe and/or persistent asthma can
be also involved in the causal mechanisms linking acceler- develop in the long-term COPD-like phenotypes. Support
ated decline of lung function in smokers with two other risk for this contention is provided by another report from the
factors: chronic bronchitis (i.e. chronic cough and phlegm) TESAOD study [19], in which adult subjects with active
and lower airway colonization/infection. Although the pre- asthma were found to have a 12 times higher risk of acquir-
dictive value of chronic bronchitis for the development of ing a diagnosis of COPD over time than subjects with no
COPD remains somewhat controversial [85, 86], this phe- asthma, after adjusting for covariates including smoking.
notype has been consistently associated with steeper rates of Since chronic airow limitation is the central hall-
FEV1 decline [87, 88]. It has been suggested that the clini- mark of COPD, much attention has been paid to under-
cal impact of chronic bronchitis may be dependent upon stand the natural history of lung function of patients who
the stage of COPD, with this phenotype having stronger develop COPD as a sequela of asthma. Much like for indi-
eects on the severe forms of COPD when lower airways viduals from the general population (Fig. 3.4), in patients
become colonized and/or infected [89]. Acute exacerbations with asthma FEV1 decits can develop mainly as a result
and lower airway colonization are strongly associated with of either lower FEV1 levels at the beginning of adult age
decline of lung function among smokers and patients with or an accelerated FEV1 decline during adulthood [51].
COPD. In a prospective study [90], patients with frequent Interestingly, most birth cohort studies including the
exacerbations (mean number of episodes per year 2.9) had Dunedin Multidisciplinary Health and Development Study
a signicantly faster decline of FEV1 than infrequent exac- [7], the Melbourne Asthma Study [36], and the British
erbators. Lower respiratory illnesses had a similar deleteri- 1958 Birth Cohort [94] have shown that, in a signicant
ous eect on decline of FEV1 over 5 years among smokers proportion of cases of persistent childhood asthma, lung
in the Lung Health Study [91]. function decits are established before the early adult years,
Of note, airway infections may also aect lung func- and track over time. These ndings, together with the obser-
tion decline through mechanisms that are independent of vation that, among children who start life with low levels
(and may indeed precede) the presence of COPD. Burrows of lung function, expiratory ows remain lower than those
and coworkers reported that smokers who recalled a history of their peers throughout childhood and adolescence [22],
of respiratory trouble before 16 years of age had signi- point toward the importance of early events in aecting
cantly steeper rates of decline in lung function as compared lung growth and/or airway remodeling in childhood and, in
with those with no such history [92]. This eect was inde- turn, in inuencing early predisposition to COPD. As for
pendent of a current or past diagnosis of asthma. It thus the second potential mechanism of lung function impair-
appears that intrinsic factors that modify the eects of ment (i.e. accelerated decline of lung function) in asthmat-
smoking may be related to events occurring during the rst ics, prospective cohort studies on adult populations have
years of life. This conclusion is compatible with the obser- provided somewhat inconsistent ndings. In the Busselton
vation by Barker and coworkers quoted earlier [64], that Health Study [95] and in the Copenhagen City Heart
elderly individuals with a history of lower respiratory illness Study [96], asthmatics showed both initial FEV1 decits
early in life were more likely to have lower levels of lung at age 20 years and an increased slope of FEV1 decline in
function than those with no such history. adulthood. However, the increase in FEV1 decline associ-
Although it is not well established how the eects of ated with asthma was only 4 ml/year in the Busselton Study.
these intrinsic and extrinsic factors on the rate of decline A possible reconciliation for these inconsistent results
of lung function are modulated, genetics are likely to play a is provided by a recent study from the TESAOD cohort.
major role. In the large cohort of the Tucson Epidemiological We identied adult participants who had FEV1/FVC ratio
Study of Airway Obstructive Disease (TESAOD), our consistently lower than 70% (as a hallmark of persistent air-
group observed signicant intra-family correlation in the ow limitation) and compared the natural history of their
rate of decline of lung function within smokers [93], sug- lung function based on the presence of asthma. Patients
gesting that these rates of decline have an important genetic with asthma accounted for about one-third of all cases of
component. However, the identication of the genetic com- persistent airow limitation. Persistent airow limitation
ponents of COPD, as well as of those of asthma, is proving was strongly associated with smoking among nonasthmat-
a challenging task and at present deciency of 1-antit- ics and with eosinophilia among subjects who had asthma
rypsin remains the only established genetic risk factor for onset  25 years. Most importantly, the natural course of
this disease.

31
Asthma and COPD: Basic Mechanisms and Clinical Management

FIG. 3.5 Natural history of lung function among participants


in the TESAOD study who had persistent airflow limitation
with or without asthma. The black line refers to subjects with
no asthma and persistent airflow limitation. The red line refers
to subjects with asthma onset  25 years and persistent
airflow limitation. The gold line refers to subjects with asthma
onset 25 years and persistent airflow limitation. Predicted
values for subjects with no asthma and no airflow limitation
(healthy controls, green line) are also reported for comparison.
Depicted values represent predicted values for a 175-cm
tall male from the best-fitting random coefficients model.
Adapted from Ref. [96].

lung function diered substantially between the two groups of their lung function impairment is already established.
(Fig. 3.5), with subjects with asthma onset  25 years Similarly, the dierent trajectories by which patients with
having lower FEV1 levels at age 25 but not steeper FEV1 traditional COPD and patients with asthma may develop
decline in adulthood as compared with expected values chronic airow limitation in their adult life support the phe-
from healthy controls. In contrast, subjects who developed notypic heterogeneity that has emerged from clinical stud-
persistent airow limitation but had no asthma showed only ies on these two groups [97]. Future research is required to
moderate FEV1 decits at age 25 years but had greater than determine whether multiple functional, morphological, and
expected FEV1 loss between age 25 and 75. Interestingly, immunological assessments can be developed to capture the
the natural course of lung function of subjects who had heterogeneity of these diseases and to identify optimal pre-
adult-onset asthma (after age 25 years) included both mod- vention and treatment strategies for these patients.
erate FEV1 decits in young adulthood and accelerated
FEV1 decline thereafter.
Taken together, ndings from this and previous stud- References
ies suggest that: (1) asthma accounts for a sizable fraction
of COPD cases at the population level; (2) while develop- 1. Burrows B, Bloom JW, Traver GA, Cline MG. The course and progno-
ment of traditional COPD is strongly associated with expo- sis of dierent forms of chronic airways obstruction in a sample from
sure to noxious agents (e.g. cigarette smoking), patients with the general population. N Engl J Med 317(21): 130914, 1987.
asthma may develop persistent airow limitation through 2. Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB.
pathways that are independent of smoking and related to The proportional Venn diagram of obstructive lung disease: Two
allergic and eosinophilic inammation; (3) among sub- approximations from the United States and the United Kingdom.
jects who had severe and/or persistent asthma in childhood Chest 124(2): 47481, 2003.
signicant decits in lung function are already present in 3. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor
early adult life; (4) during adulthood accelerated decline of for COPD in a longitudinal study. Chest 126(1): 5965, 2004.
4. Pauwels RA, Buist AS, Calverley PM, Jenkin CR, Hurd SS. Global
FEV1 might be present for subgroups of asthmatics, but this
strategy for the diagnosis, management, and prevention of chronic
accelerated decline is likely to account for a limited propor- obstructive pulmonary disease. NHLBI/WHO Global Initiative for
tion of the asthma-related decits in lung function up to Chronic Obstructive Lung Disease (GOLD) Workshop summary.
mid-adult life; (5) childhood versus adult-onset asthma may Am J Respir Crit Care Med 163(5): 125676, 2001.
be associated with a dierent natural history of lung func- 5. Martinez FD. Context dependency of markers of disease. Am J Respir
tion that might explain part of the inconsistencies of results Crit Care Med 162(2 Pt 2): S56S57, 2000.
on FEV1 decline in asthmatics across dierent studies. 6. Barbee RA, Dodge R, Lebowitz ML, Burrows B. The epidemiology of
The implications of these conclusions for prevention asthma. Chest 87(1 Suppl): 21S25S, 1985.
and treatment are crucial because they indicate that the tim- 7. Sears MR, Greene JM, Willan AR et al. A longitudinal, population-
based, cohort study of childhood asthma followed to adulthood. N Engl
ing and nature of prevention strategies for COPD-like phe-
J Med 349(15): 141422, 2003.
notypes need to be dierent for subjects with and without 8. Strachan DP, Butland BK, Anderson HR. Incidence and prognosis
asthma. While smoking prevention and cessation is vital of asthma and wheezing illness from early childhood to age 33 in a
against inception of traditional COPD, any intervention to national British cohort. BMJ 312(7040): 119599, 1996.
prevent development of persistent airow limitation among 9. Oswald H, Phelan PD, Lanigan A, Hibbert M, Bowes G, Olinsky A.
patients with childhood asthma will need to target these Outcome of childhood asthma in mid-adult life. BMJ 309(6947):
patients before they enter adult life because by then the bulk 9596, 1994.

32
Natural History 3
10. Jenkins MA, Hopper JL, Bowes G, Carlin JB, Flander LB, Giles most province of Sweden: Schools as a major site of exposure. J Allergy
GG. Factors in childhood as predictors of asthma in adult life. BMJ Clin Immunol 103(6): 101824, 1999.
309(6947): 9093, 1994. 32. Crestani E, Guerra S, Wright AL, Halonen M, Martinez FD. Parental
11. Anderson HR, Pottier AC, Strachan DP. Asthma from birth to age 23: asthma as a risk factor for the development of early skin test sensitiza-
Incidence and relation to prior and concurrent atopic disease. Thorax tion in children. J Allergy Clin Immunol 113(2): 28490, 2004.
47(7): 53742, 1992. 33. Martinez FD, Stern DA, Wright AL, Holberg CJ, Taussig LM,
12. Guerra S, Wright AL, Morgan WJ, Sherrill DL, Holberg CJ, Martinez Halonen M. Association of interleukin-2 and interferon-gamma pro-
FD. Persistence of asthma symptoms during adolescence: Role of obes- duction by blood mononuclear cells in infancy with parental allergy
ity and age at the onset of puberty. Am J Respir Crit Care Med 170(1): skin tests and with subsequent development of atopy. J Allergy Clin
7885, 2004. Immunol 96(5 Pt 1): 65260, 1995.
13. Yunginger JW, Reed CE, OConnell EJ, Melton LJ III, OFallon WM, 34. Stern DA, Guerra S, Halonen M, Wright AL, Martinez FD. Low
Silverstein MD. A community-based study of the epidemiology of asthma. IFN-gamma production in the rst year of life as a predictor of wheeze
Incidence rates, 19641983. Am Rev Respir Dis 146(4): 88894, 1992. during childhood. J Allergy Clin Immunol 120(4):83541.
14. Stein RT, Sherrill D, Morgan WJ et al. Respiratory syncytial virus 35. Guerra S, Lohman IC, Halonen M, Martinez FD, Wright AL.
in early life and risk of wheeze and allergy by age 13 years. Lancet Reduced interferon gamma production and soluble CD14 levels in
354(9178): 54145, 1999. early life predict recurrent wheezing by 1 year of age. Am J Respir Crit
15. Stein RT, Holberg CJ, Morgan WJ et al. Peak ow variability, metha- Care Med 169(1): 7076, 2004.
choline responsiveness and atopy as markers for detecting dierent 36. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study:
wheezing phenotypes in childhood. Thorax 52(11): 94652, 1997. 19641999. J Allergy Clin Immunol 109(2): 18994, 2002.
16. Martinez FD, Helms PJ. Types of asthma and wheezing. Eur Respir J 37. Horak E, Lanigan A, Roberts M et al. Longitudinal study of childhood
Suppl 27: 3s8s, 1998. wheezy bronchitis and asthma: Outcome at age 42. BMJ 326(7386):
17. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy. 42223, 2003.
Eects on lung function during the rst 18 months of life. Am J Respir 38. Marossy AE, Strachan DP, Rudnicka AR, Anderson HR. Childhood
Crit Care Med 152(3): 97783, 1995. chest illness and the rate of decline of adult lung function between ages
18. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM. 35 and 45 years. Am J Respir Crit Care Med 175(4): 35559, 2007.
Diminished lung function as a predisposing factor for wheezing respi- 39. Williams H, McNicol KN. Prevalence, natural history, and relationship
ratory illness in infants. N Engl J Med 319(17): 111217, 1988. of wheezy bronchitis and asthma in children. An epidemiological study.
19. Martinez FD. Sudden infant death syndrome and small airway occlu- BMJ 4(5679): 32125, 1969.
sion: Facts and a hypothesis. Pediatrics 87(2): 19098, 1991. 40. Phelan PD. Asthma in Children and Adolescents: An Overview. .
20. Montgomery GL, Tepper RS. Changes in airway reactivity with age London: Baillire Tindall, 1995.
in normal infants and young children. Am Rev Respir Dis 142(6 Pt 1): 41. Camargo CA Jr., Weiss ST, Zhang S, Willett WC, Speizer FE.
137276, 1990. Prospective study of body mass index, weight change, and risk of
21. Burrows B, Sears MR, Flannery EM, Herbison GP, Holdaway MD, adult-onset asthma in women [see comments]. Arch Intern Med
Silva PA. Relation of the course of bronchial responsiveness from age 159(21): 258288, 1999.
9 to age 15 to allergy. Am J Respir Crit Care Med 152(4 Pt 1): 13028, 42. Castro-Rodriguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez
1995. FD. Increased incidence of asthmalike symptoms in girls who become
22. Morgan WJ, Stern DA, Sherrill DL et al. Outcome of asthma and overweight or obese during the school years. Am J Respir Crit Care Med
wheezing in the rst 6 years of life: Follow-up through adolescence. 163(6): 134449, 2001.
Am J Respir Crit Care Med 172(10): 125358, 2005. 43. Beuther DA, Sutherland ER. Overweight, obesity, and incident
23. Zeiger RS, Dawson C, Weiss S. Relationships between duration of asthma: A meta-analysis of prospective epidemiologic studies. Am J
asthma and asthma severity among children in the Childhood Asthma Respir Crit Care Med 175(7): 66166, 2007.
Management Program (CAMP). J Allergy Clin Immunol 103(3 Pt 1): 44. Guerra S, Sherrill DL, Bobadilla A, Martinez FD, Barbee RA. The
37687, 1999. relation of body mass index to asthma, chronic bronchitis, and emphy-
24. Halonen M, Stern DA, Lohman C, Wright AL, Brown MA, Martinez sema. Chest 122(4): 125663, 2002.
FD. Two subphenotypes of childhood asthma that dier in maternal 45. Taylor DR, Cowan JO, Greene JM, Willan AR, Sears MR. Asthma
and paternal inuences on asthma risk. Am J Respir Crit Care Med in remission: can relapse in early adulthood be predicted at 18 years of
160(2): 56470, 1999. age? Chest 127(3): 84550, 2005.
25. Halonen M, Stern DA, Wright AL, Taussig LM, Martinez FD. 46. Vonk JM, Postma DS, Boezen HM et al. Childhood factors associated with
Alternaria as a major allergen for asthma in children raised in a desert asthma remission after 30 year follow up. Thorax 59(11): 92529, 2004.
environment. Am J Respir Crit Care Med 155(4): 135661, 1997. 47. van Den Toorn LM, Prins JB, Overbeek SE, Hoogsteden HC,
26. Pullan CR, Hey EN. Wheezing, asthma, and pulmonary dysfunction de Jongste JC. Adolescents in clinical remission of atopic asthma have
10 years after infection with respiratory syncytial virus in infancy. BMJ elevated exhaled nitric oxide levels and bronchial hyperresponsiveness.
(Clin Res Ed) 284(6330): 166569, 1982. Am J Respir Crit Care Med 162(3 Pt 1): 95357, 2000.
27. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. 48. van den Toorn LM, Overbeek SE, de Jongste JC, Leman K,
Association of asthma with serum IgE levels and skin-test reactivity to Hoogsteden HC, Prins JB. Airway inammation is present during
allergens. N Engl J Med 320(5): 27177, 1989. clinical remission of atopic asthma. Am J Respir Crit Care Med 164(11):
28. Peat JK, Tovey E, Toelle BG et al. House dust mite allergens. A major 210713, 2001.
risk factor for childhood asthma in Australia. Am J Respir Crit Care 49. Warke TJ, Fitch PS, Brown V et al. Outgrown asthma does not mean
Med 153(1): 14146, 1996. no airways inammation. Eur Respir J 19(2): 28487, 2002.
29. Dust mite allergens and asthmaa worldwide problem. J Allergy Clin 50. Rabe KF, Hurd S, Anzueto A et al. Global strategy for the diagnosis,
Immunol 83(2 Pt 1): 41627, 1989. management, and prevention of COPD-2006 Update. Am J Respir Crit
30. Peat JK, Tovey E, Mellis CM, Leeder SR, Woolcock AJ. Importance Care Med, 2007.
of house dust mite and Alternaria allergens in childhood asthma: An 51. Weiss ST, Ware JH. Overview of issues in the longitudinal analysis of
epidemiological study in two climatic regions of Australia. Clin Exp respiratory data. Am J Respir Crit Care Med 154(6 Pt 2): S208S211,
Allergy 23(10): 81220, 1993. 1996.
31. Perzanowski MS, Ronmark E, Nold B, Lundback B, Platts-Mills TA. 52. Stocks J. Lung function testing in infants. Pediatr Pulmonol Suppl 18:
Relevance of allergens from cats and dogs to asthma in the northern- 1420, 1999.

33
Asthma and COPD: Basic Mechanisms and Clinical Management

53. Le Souef P, Turner S, Rye P et al. Pulmonary function at four weeks 74. Camilli AE, Burrows B, Knudson RJ, Lyle SK, Lebowitz MD.
correlates with pulmonary function at 6 and 12 years. Am J Respir Crit Longitudinal changes in forced expiratory volume in one second in
Care Med 163: A541, 2001. adults. Eects of smoking and smoking cessation. Am Rev Respir Dis
54. Turner SW, Palmer LJ, Rye PJ et al. The relationship between infant 135(4): 79499, 1987.
airway function, childhood airway responsiveness, and asthma. Am J 75. Pauwels RA, Rabe KF. Burden and clinical features of chronic obstruc-
Respir Crit Care Med 169(8): 92127, 2004. tive pulmonary disease (COPD). Lancet 364(9434): 61320, 2004.
55. Stern DA, Morgan WJ, Wright AL, Guerra S, and Martinez FD. Poor 76. Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic
aiway function in early infancy and lung function by age 22 years: a non- obstructive pulmonary disease. Eur Respir J 17(5): 98294, 2001.
selective longitudinal cohort study. Lancet 370(9589): 75864, 2007. 77. Rennard SI, Vestbo J. COPD: The dangerous underestimate of 15%.
56. Young S, Arnott J, OKeee PT, Le Souef PN, Landau LI. The associa- Lancet 367(9518): 121619, 2006.
tion between early life lung function and wheezing during the rst 2 78. Fletcher CM, Peto CM, Tinker CM, Spizer FE. The Natural History
yrs of life. Eur Respir J 15(1): 15157, 2000. of Chronic Bronchitis and Emphysema. New York: Oxford University
57. Pagtakhan RD, Bjelland JC, Landau LI et al. Sex dierences in growth Press, 1976.
patterns of the airways and lung parenchyma in children. J Appl Physiol 79. Orie NGM, Sluiter HJ, de Vries K, Tammeling GJ, Witkop J. The
56(5): 120410, 1984. host factor in bronchits. In: Orie NGM, Sluiter HJ (eds). Bronchitis an
58. Stein RT, Holberg CJ, Sherrill D et al. Inuence of parental smoking International Symposium. Assen, Netherlands: Royal vanGorcum, 1961.
on respiratory symptoms during the rst decade of life: The Tucson 80. Sluiter HJ, Koeter GH, de Monchy JG, Postma DS, de Vries K, Orie NG.
Childrens Respiratory Study. Am J Epidemiol 149(11): 103037, The Dutch hypothesis (chronic non-specic lung disease) revisited. Eur
1999. Respir J 4(4): 47989, 1991.
59. Tager IB, Hanrahan JP, Tosteson TD et al. Lung function, pre- and 81. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA.
post-natal smoke exposure, and wheezing in the rst year of life. Methacholine reactivity predicts changes in lung function over time in
Am Rev Respir Dis 147(4): 81117, 1993. smokers with early chronic obstructive pulmonary disease. The Lung
60. Murray CS, Pipis SD, McArdle EC, Lowe LA, Custovic A, Woodcock Health Study Research Group. Am J Respir Crit Care Med 153(6 Pt 1):
A. Lung function at one month of age as a risk factor for infant res- 180211, 1996.
piratory symptoms in a high risk population. Thorax 57(5): 38892, 82. Brutsche MH, Downs SH, Schindler C et al. Bronchial hyperrespon-
2002. siveness and the development of asthma and COPD in asymptomatic
61. Haland G, Carlsen KC, Sandvik L et al. Reduced lung function at individuals: SAPALDIA cohort study. Thorax 61(8): 67177, 2006.
birth and the risk of asthma at 10 years of age. N Engl J Med 355(16): 83. Rijcken B, Schouten JP, Xu X, Rosner B, Weiss ST. Airway hyperre-
168289, 2006. sponsiveness to histamine associated with accelerated decline in FEV1.
62. Burrows B, Knudson RJ, Lebowitz MD. The relationship of childhood Am J Respir Crit Care Med 151(5): 137782, 1995.
respiratory illness to adult obstructive airway disease. Am Rev Respir 84. Postma DS, de Vries K, Koeter GH, Sluiter HJ. Independent inuence
Dis 115(5): 75160, 1977. of reversibility of air-ow obstruction and nonspecic hyperreactivity
63. Samet JM, Tager IB, Speizer FE. The relationship between respiratory on the long-term course of lung function in chronic air-ow obstruc-
illness in childhood and chronic air-ow obstruction in adulthood. tion. Am Rev Respir Dis 134(2): 27680, 1986.
Am Rev Respir Dis 127(4): 50823, 1983. 85. Vestbo J, Lange P. Can GOLD Stage 0 provide information of prog-
64. Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. nostic value in chronic obstructive pulmonary disease? Am J Respir Crit
Relation of birth weight and childhood respiratory infection to adult Care Med 166(3): 32932, 2002.
lung function and death from chronic obstructive airways disease. BMJ 86. de Marco R, Accordini S, Cerveri T et al. Incidence of chronic obstruc-
303(6804): 67175, 1991. tive pulmonary disease in a cohort of young adults according to the
65. Edwards CA, Osman LM, Godden DJ, Campbell DM, Douglas JG. presence of chronic cough and phlegm. Am J Respir Crit Care Med
Relationship between birth weight and adult lung function: Controlling 175(1): 3239, 2007.
for maternal factors. Thorax 58(12): 106165, 2003. 87. Sherman CB, Xu X, Speizer FE, Ferris BG Jr, Weiss ST, Dockery DW.
66. Lawlor DA, Ebrahim S, Davey Smith G. Association of birth weight Longitudinal lung function decline in subjects with respiratory symp-
with adult lung function: Findings from the British Womens Heart toms. Am Rev Respir Dis 146(4): 85559, 1992.
and Health Study and a meta-analysis. Thorax 60(10): 85158, 2005. 88. Vestbo J, Prescott E, Lange P. Association of chronic mucus hyperse-
67. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in cretion with FEV1 decline and chronic obstructive pulmonary disease
subjects with asthma. Eur J Respir Dis 70(3): 17179, 1987. morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care
68. Agertoft L, Pedersen S. Eects of long-term treatment with an inhaled Med 153(5): 153035, 1996.
corticosteroid on growth and pulmonary function in asthmatic chil- 89. Vestbo J, Hogg JC. Convergence of the epidemiology and pathology of
dren. Respir Med 88(5): 37381, 1994. COPD. Thorax 61(1): 8688, 2006.
69. Long-term eects of budesonide or nedocromil in children with 90. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA.
asthma. The Childhood Asthma Management Program Research Relationship between exacerbation frequency and lung function decline
Group. N Engl J Med 343(15): 105463, 2000. in chronic obstructive pulmonary disease. Thorax 57(10): 84752, 2002.
70. Guilbert TW, Morgan WJ, Zeiger RS et al. Long-term inhaled corti- 91. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses
costeroids in preschool children at high risk for asthma. N Engl J Med promote FEV(1) decline in current smokers but not ex-smokers with
354(19): 198597, 2006. mild chronic obstructive pulmonary disease: results from the lung
71. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, health study. Am J Respir Crit Care Med 164(3): 35864, 2001.
Morgan WJ. Asthma and wheezing in the rst six years of life. The 92. Burrows B, Knudson RJ, Cline MG, Lebowitz MD. A reexamination
Group Health Medical Associates. N Engl J Med 332(3): 13338, of risk factors for ventilatory impairment. Am Rev Respir Dis 138(4):
1995. 82936, 1988.
72. Xuan W, Peat JK, Toelle BG, Marks GB, Berry G, Woolcock AJ. 93. Kurzius-Spencer M, Sherrill DL, Holberg CJ, Martinez FD,
Lung function growth and its relation to airway hyperresponsiveness Lebowitz MD. Familial correlation in the decline of forced expiratory
and recent wheeze. Results from a longitudinal population study. Am J volume in one second. Am J Respir Crit Care Med 164(7): 126165,
Respir Crit Care Med 161(6): 182024, 2000. 2001.
73. Holberg CJ, Stern DA, Sherrill DL, Wright AL, Martinez FD, 94. Marossy AE, Strachan DP, Rudnicka AR, Anderson HR. Childhood
Morgan WJ. Eect of smoking on the development of lung function in Chest Illness and the Rate of Decline of Adult Lung Function
adolescence. Am J Respir Crit Care Med 163: A260, 2001. Between Ages 35 and 45 Years. Am J Respir Crit Care Med, 2006.

34
Natural History 3
95. James AL, Palmer LJ, Kicic E et al. Decline in lung function in the 97. Fabbri LM, Romagnoli M, Corbetta L et al. Dierences in airway
Busselton Health Study: The eects of asthma and cigarette smoking. inammation in patients with xed airow obstruction due to asthma
Am J Respir Crit Care Med 171(2): 10914, 2005. or chronic obstructive pulmonary disease. Am J Respir Crit Care Med
96. Guerra S, Sherrill DL, Kurzius-Spencer M, Venker C, Halonen M, 167(3): 41824, 2003.
Quan SF, Martinez FD. The course of persistent airow limitation in
subjects with and without asthma. Respir Med (in press).

35
Genetics of Asthma and COPD
4
CHAPTER

INTRODUCTION if they smoke cigarettes. However, the develop- Dirkje S. Postma1 and
ment of COPD among PI ZZ subjects is highly Edwin K. Silverman2
variable, and environmental, developmental, and
It is now a well-established fact that genetic fac- genetic factors likely contribute to this variabil- 1
Department of Pulmonology,
tors contribute to the development of asthma and ity. DeMeo and colleagues recently conrmed University Medical Center Groningen,
chronic obstructive pulmonary disease (COPD). that male gender and asthma (especially in University of Groningen, Groningen,
This chapter sets out the current knowledge childhood), as well as cigarette smoking, are risk The Netherlands
focusing on the heritability of asthma and factors for COPD in PI ZZ subjects [3]. 2
Channing Laboratory and Division of
COPD and the genes found by positional clon- Evidence that COPD unrelated to AAT Pulmonary and Critical Care Medicine,
ing and association studies. It also focuses on par- deciency is also inuenced by genetic factors
ticular genes to provide insight into the current Brigham and Womens Hospital, Harvard
has been provided by many familial aggregation
knowledge on genetic approaches to understand- Medical School, Boston, MA, USA
studies. Pulmonary function levels in the general
ing diseases like asthma and COPD. population cluster in families [4]. Moreover, stud-
ies of relatives of COPD subjects have conrmed
familial aggregation of COPD, probably related
to gene-by-smoking interactions. Silverman and
HERITABILITY OF ASTHMA AND COPD colleagues found that rst-degree relatives of
severe, early-onset COPD subjects who smoke,
had an approximately threefold increased risk
It has been known for centuries that asthma of airow obstruction and chronic bronchitis
clusters in families (familial aggregation). [5]; nonsmoking relatives had increased risk for
The rst segregation studies in families abnormalities in sensitive spirometric measures
with an asthmatic proband already showed that such as FEF25-75 but not for severe airow
no single-gene accounts for a major part of the obstruction [6]. McCloskey and colleagues con-
expression of the disease. A polygenic model rmed that COPD showed familial aggregation,
with some evidence of oligogenic loci (i.e. a which was only apparent in smokers [7]. Multiple
handful of loci being responsible for most of genes likely contribute to the susceptibility for
the genetic control) provided the best t to the COPD and its phenotypic expression.
data [1]. In the studies of the heritability of asthma
For COPD, a role for genetic factors has and COPD, the absence of unambiguous crite-
been less obvious, because cigarette smoking ria for their diagnosis and the fact that asthma
is such a major environmental risk factor. The and COPD are not one disease entity but are
identication of alpha 1-antitrypsin (AAT) both heterogeneous diseases, for example
deciency in the 1960s proved that genes could COPD can encompass both chronic bronchitis
inuence COPD susceptibility [2]. AAT de- and emphysema and the latter occurs homoge-
ciency is largely caused by homozygosity for neously or locally in the lung, have been major
the Z allele (PI ZZ) at the SERPINA1 locus, obstacles to pinpointing the exact polymor-
although multiple other rare deciency alle- phisms in genes contributing to disease devel-
les have been identied. PI ZZ subjects are at opment. Another explanation for the failure to
markedly increased risk for COPD, especially identify loci may lie in the genetic component

37
Asthma and COPD: Basic Mechanisms and Clinical Management

of the disease. For instance, dierent genes can be involved Candidate genes of unknown function or unknown
in the same phenotype (genetic heterogeneity) or the role in disease pathogenesis can also be selected for genetic
same genotype may result in dierent phenotypes (pleiot- analysis based on their dierential expression in diseased
ropy). Mutated genes do not always express the phenotype versus normal tissue [10, 11]. Another approach is to select
(incomplete penetrance) and vice versa. The specic phe- a gene that is a proven cause of a monogenic syndrome
notype under study can be expressed without the genetic that has the disease of interest as a component of its syn-
mutation (phenocopy). drome constellation. The hypothesis that can be tested is
that mutations in the gene with a milder functional eect
can contribute to the development of a complex genetic
disorder in the general population. The gene SPINK5 that
ASSESSING GENES FOR ASTHMA AND COPD encodes the serine protease inhibitor LEKTI on chromo-
some 5q32 as the cause of Netherton syndrome is such an
example [12]. Netherton syndrome is a severe autosomal
The human genome consists of approximately 3 billion base recessive disorder with a congenital skin disease associ-
pairs. The sequence of the whole human genome has recently ated with defective cornication and severe atopic mani-
been published [8]. The genetic distances are expressed in festations. A common coding polymorphism of SPINK5,
centiMorgans (cM). One cM is about 100,000 base pairs on E420K, has been shown to be associated with atopy and
a physical map and corresponds to 1% recombination during atopic dermatitis in two independent family cohorts [13],
meiosis. This means that one crossing-over event between although replication attempts have had varying success [14,
two loci that are one cM apart occurs in every hundred 15]. In COPD, cutis laxa is a rare dermatological syndrome
meioses. The estimation of the total number of genes in the related to abnormal connective tissue elasticity; some cases
human genome is about 20,000 [9]. Most genes in the pop- are caused by mutations in the distal part of the elastin
ulation have multiple locations where more than one variant (ELN) gene. Emphysema often occurs in cutis laxa at a very
is commonly found; the variants at these polymorphic loca- early age. Kelleher and colleagues found a rare mutation
tions are known as alleles. Only a minority of human DNA in the rst base of the last exon of ELN in an early-onset
is responsible for the coding for a biological product. COPD subject [16]. This variant, which was not a private
The main strategies to identify susceptibility genes are mutation in that pedigree, interfered with the assembly of
positional cloning and the candidate gene approach. the elastic ber, changed the proteolytic pattern of the ELN
Positional cloning starts with the investigation of protein, and altered cellular adhesion of the ELN molecule.
families without a predetermined hypothesis regarding the Thus, in both asthma and COPD, the assessment of can-
location or identity of the underlying susceptibility gene or didate genes from monogenic syndromes has led to some
genes. Markers are randomly spaced throughout the entire insights into the disease etiology.
genome and tested for linkage (i.e. coinheritance) with a Both the positional cloning and the candidate gene
disease phenotype. After the nding of linkage between a approaches have their own limitations. Population associa-
particular marker and a phenotype, further ne spaced typ- tion between a disease and a genetic marker can arise as an
ing of genetic markers (ne mapping) is required to pin- artifact of the population structure. Linkage studies with
point the exact gene causing the linkage. The approach is modest numbers of aected sib pairs may be underpowered
time consuming, as in-depth analysis of a particular region and fail to detect linkage, especially if there is genetic het-
of linkage that still can cover a large part of a chromosome, erogeneity. Furthermore, although linkage analysis has been
requires considerable molecular analysis. successful to identify genes underlying single-gene disor-
An alternative approach is to select candidate genes ders, in complex diseases it is frequently very dicult to
that putatively contribute to the underlying pathological suciently narrow a region of linkage to just a single gene.
process of the disease. The gene is screened for polymor- Nevertheless positional cloning in asthma has identied
phisms, which are tested for association with the disease some genes.
or phenotype in question. The results can be interpreted in A truly comprehensive genetic association study must
three ways, as shown in Box 4.1. consider all putative causal alleles in a gene of interest or
Replication of any genetic study is required to exclude in the entire human genome if resources are available. Until
spurious ndings especially if multiple genes are involved in recently, this was practically impossible. With the comple-
the disease process, like in asthma and COPD. tion of the International HapMap Project [17], it is now

Box 4.1. POTENTIAL CAUSES OF GENOTYPEPHENOTYPE ASSOCIATION


1. The trait of interest is due to a genotyped variant in the candidate gene.
2. The trait is determined by one or more genetic variants in linkage disequilibrium with a genotyped variant; that is, a
genotyped variant is very close to the disease gene.
3. The association is the result of population admixture, that is, a certain trait has a higher prevalence in a specic ethnic
subgroup within a mixed population. Any allele with a higher frequency within this subgroup will show association
with the trait.

38
Genetics of Asthma and COPD 4
possible to target a large proportion of the genetic variation the linkage between the markers and a hypothetical disease
across the genome, either directly or indirectly (via LD). susceptibility locus is determined. The evidence for linkage
HapMap is a freely available reference panel of genotype is often expressed as an LOD score, which is the logarithm
data from dierent worldwide populations (http://www. to the base 10 of the odds for linkage. Depending on the
hapmap.org). This resource can be used to guide the design study design, LOD scores above 3.3 (for extended pedi-
of disease association studies and prioritization of single grees) or 3.6 (for sib pairs) correspond to signicant linkage
nucleotide polymorphism (SNP) genotyping assays. With [23]. Although the location of genes for classic Mendelian
this dataset, it is possible to study genetic variants for any disorders can usually be determined quite accurately by
locus of interest. The HapMap dataset has clearly demon- linkage analysis, the locations of complex disease suscepti-
strated the existence of correlations between nearby variants. bility loci are typically less precisely localized due to genetic
By taking advantage of these correlations, one can select heterogeneity, incomplete penetrance, and environmental
informative SNPs (tagging SNPs) that provide information phenocopies. Linkage can be assessed for quantitative phe-
about neighboring variants that are not genotyped. Only a notypes as well as disease aection status.
small fraction of SNPs need to be genotyped to capture the A large number of genome scan linkage studies have
full information in a specic region. If a causal variant is not been performed in asthma, which were summarized by
genotyped, its eect can be indirectly tested with the corre- Celedon and colleagues [24]. Based on follow-up studies
lated tag SNP that has been genotyped. after linkage analyses, six potential susceptibility genes for
The single-gene approach described earlier can also asthma have been reported using positional cloning [2530].
be extended to the entire genome. Genome-wide asso- The only published genome scan linkage studies in COPD
ciation scans are emerging as powerful tools to identify have been performed in the Boston Early-Onset COPD
genes involved in complex diseases. On the basis of phase Study, implicating chromosomes 2q, 12p, and 19q as likely
I HapMap data, it was shown that approximately 250,000 locations of COPD susceptibility genes [31, 32]. Of interest,
500,000 SNPs are required to capture all common SNPs a linkage study of spirometric phenotypes in a set of families
in human populations. Although these numbers appear unselected for respiratory disease identied chromosome
impressive, current technologies can evaluate 1,000,000 2q, a location of signicant linkage to COPD, and chromo-
SNPs simultaneously [18, 19]. By selecting SNPs properly, some 5q, a location of signicant linkage to asthma, as likely
we can now interrogate the entire genome in one assay. This locations for genetic inuences on FEV1/FVC in the gen-
allows us to undertake genome-wide association studies, eral population [33]. In an adjacent region on chromosome
combining the ne mapping and power of association anal- 2q, Postma and colleagues found signicant evidence for
ysis and the ease of casecontrol cohort recruitment with linkage to FEV1/VC in families ascertained through asth-
a genome-wide hypothesisindependent approach. These matic probands [34]. Thus, there may be genetic inuences
promising tools will certainly have a major impact on our on asthma, COPD, and pulmonary function in the general
understanding of the genetic basis of complex diseases such population located within chromosome 2q.
as asthma and COPD. Genome-wide association stud-
ies have already led to important and novel insights into
the genetic architecture of a rapidly expanding list of com-
plex diseases, including age-related macular degeneration
and adult-onset diabetes mellitus [20, 21]. Although not ASSOCIATION STUDIES IN ASTHMA AND COPD
yet reported in COPD, Moatt and colleagues have per-
formed a genome-wide association analysis in asthma [22]. A large number of SNPs in the promoters and coding
They identied a region of highly signicant association to regions of a wide range of candidate genes have been exam-
asthma on chromosome 17q, which was replicated in sev- ined for genetic association in asthma. There are now over
eral other study populations. Using microarray gene expres- 500 studies that have examined polymorphisms in over 200
sion data, they observed that the expression of one of the genes for association with atopy and allergic disease pheno-
genes in that region, ORMDL3, was strongly associated types [3537]. These studies have provided us with increas-
with the same SNPs that were associated with asthma ing insight into genetic susceptibility to asthma, the role of
suggesting that asthma susceptibility is related to ORMDL3 geneenvironment interaction and the role of genetic varia-
gene expression. tion in inter-individual response to treatment.
In this part we will focus on ve of the candidate genes
that have the best evidence for involvement in asthma sus-
ceptibility (Table 4.1); these genes have been identied in
LINKAGE ANALYSIS OF ASTHMA AND COPD various ways, including positional cloning (ADAM33) and
positional and/or biological candidates (IL-13, IL-4, IL-4R,
CD-14). We will also review an example from asthma phar-
Linkage analysis includes a group of genetic epidemiologi- macogenetics (ADRB2).
cal methods that are used to identify chromosomal regions Subsequently, we will consider ve of the COPD
that are likely to contain one or more genetic determinants candidate genes with the strongest evidence for associa-
inuencing a phenotype of interest. A panel of genetic tion to COPD susceptibility, including positional candi-
markers is genotyped within family units, which can be dates (TGFB1 and SERPINE2) and biological candidates
as small as sib pairs or as large as extended pedigrees, and (GSTP1, EPHX1, and SOD3) (Table 4.2).

39
Asthma and COPD: Basic Mechanisms and Clinical Management

TABLE 4.1 Summary of positive and negative association studies in the genes ADAM33, IL-3, IL-4, and IL-4R with asthma and its related phenotypes.

Studies supporting Studies refuting


Gene association association Comments

A disintegrin and [25] Caucasian [38] Puerto Rican,


metalloprotease Mexican
33 (ADAM33) [39] African Americans, [40] Raby children
Caucasian, Hispanic, Dutch
[41] Japanese [42] Chinese Cheng allergic rhinitis
[43] ) Korean [44] German Schedel children. Positive and negative associations with various phenotypes
[45] Caucasian Jongepier association with FEV1 decline
[46] Caucasian
[47] Caucasian Simpson low lung function in children
[48]
[49] Japanese Noguchi children

IL-13, IL-4, IL-4R [50] [51] Celedon IL-13 83 trios children


Deichmann IL-13, IL-4R
[52] IL-13
[53] IL-13
[54] IL-13  Children
[55] IL-13  Children
[56] IL-4R /IL-4Children
[57] IL-13 /IL-4R
[56] IL-4R
[53] IL-13
[58] IL-13, IL-4 Interaction
[59] IL-13 Children
[60] IL-13
[61] IL-4R
[62] IL-13/IL-4R Interaction
[63] IL-13 Children
[64] IL-13/IL-4 Children
[65] IL-13/Il-4/IL-4R Children, Interaction
[66] IL-4/IL-4R Interaction
[67] IL-13 Children
[68) IL-4/ IL-4R Children
[69] Children
[70] IL-13
[71]
[72] IL-13/IL-4/IL-4RInteraction Children
[73] IL-4R/IL-13 Interaction  Children
[74] IL-13 Children

SNPs in the IL13/IL4 pathway have been reported as single gene association. When interaction was present, this has been assigned as interaction, and when interaction was
absent, this has been assigned as interaction .

ASTHMA GENETIC ASSOCIATION STUDIES [25]. Multiple SNPs within ADAM33 were signicantly
associated with asthma and BHR in a US or UK popula-
tion, or with these two populations combined. The nomen-
Gene found by positional cloning: ADAM33 clature typically used for ADAM33 SNPs is unusual; the
exons have been assigned sequential letters, and the SNPs
ADAM33 was discovered by positional cloning in 460 have been sequentially numbered within each exon (e.g. S_2
Caucasian families from the US and UK on chromosome is the second SNP in exon S). SNPs occurring in the intron
20p. It was associated with asthma, specically when bron- before an exon are designated with a minus sign (e.g. Q-1
chial hyperresponsiveness (BHR) was present, and there is an intronic SNP before exon Q), and SNPs occurring in
were variations in total and as well as specic IgE levels an intron immediately after an exon are designated with

40
Genetics of Asthma and COPD 4
TABLE 4.2 Summary genetic association evidence for five candidate genes in COPD.

Studies supporting Studies refuting


Gene association association Comments

Microsomal epoxide hydrolase (EPHX1) [75] [76] Yoshikawa reported association with COPD severity
[77] [78]
[79] [80]
[81] [81] Hersh found association in their case-control study but
not their family study
[82] Cheng reported association with COPD severity

Glutathione S-transferase P1 (GSTP1) [83] [84]


[85] [81] He found increased risk for Val105 as opposed to Ile105
[86] [82] Cheng found increased COPD risk for combination of
Ile105 with GSTM1 and EPHX1 variants

Extracellular superoxide dismutase (SOD3) [87] Arg213Gly variant has low frequency
[88]

Transforming growth factor beta 1 (TGFB1) [89] [90]


[91] [92]
[93]
[94] Van Diemen found association with COPD affection
status but not FEV1 decline

Serpin peptidase inhibitor, Clade E, Member [95] [96]


2 (SERPINE2)
[97]

a plus sign (e.g. F  1 is an intronic SNP after exon F). level [99]. A total of 1390 subjects from a Dutch general
The majority of associated SNPs were located in the 3
population cohort were genotyped for eight asthma-
half of the gene, extending from exon Q to the last exon, associated SNPs. Individuals homozygous for the minor
exon V. Subsequently, there have been a large number of alleles of SNPs S_2 and Q-1 and heterozygous for the
casecontrol and family-based association studies focused SNP S_1 had a signicantly accelerated FEV1 decline over
on ADAM33, with the majority [39, 43, 45, 46, 48, 49, 82] 25 years follow-up of 4.9, 9.6, and 3.6 ml/year, respectively,
but not all [38, 40, 42, 44], conrming the original nding when compared with the wild-type allele. A further analysis
(Table 4.1). For example, the Collaborative Study on the demonstrated a higher prevalence of the SNPs F  1, S_1,
Genetics of Asthma, comprising eight US genetic cent- S_2, ST  5, and T_2 in subjects with COPD at GOLD
ers, demonstrated positive association between SNPs in (Global Initiative for Chronic Obstructive Lung Disease)
ADAM33 and asthma as well as BHR in African-American, stage II or higher. Thus, in addition to asthma, it seems that
Hispanic, and white populations [39]. In a further study polymorphic variation in ADAM33 also inuences the rate
involving 1299 asthma cases, 1665 control subjects, and of decline of lung function at a population level, which may
4561 family members, Blakey and colleagues [48] applied then lead to COPD. Subsequently, the authors conrmed
a literature-based meta-analysis, which supplemented the association with COPD in a second cohort [100] and
the database with new asthma cases from populations in interestingly found that the same ST_5 SNP was associ-
Iceland and the United Kingdom, and demonstrated sig- ated with the severity of BHR in COPD patients, as well
nicant association for 4 of the 13 SNPs tested. as to the number of sputum cells and CD8 cells in bron-
It is well recognized that in patients with chronic per- chial biopsies. This links the increase in cells in COPD with
sistent asthma, baseline lung function declines more rapidly hyperresponsiveness and ADAM33.
over time when compared with that of normal individuals Finally, the Manchester Asthma and Allergy Study,
[98]. Jongepier et al. showed in 200 patients with chronic a prospective cohort study of the development of asthma
asthma who were studied annually for 25 years [45] that and allergies in children, investigated the relation between
the rare allele of the S_2 polymorphism (minor allele fre- SNPs in ADAM33 and lung function at ages 3 and 5 [47].
quency 0.25) was signicantly associated with excess At the age of 5 years, four of the SNPs were associated
decline in FEV1 over time and concluded that this variant with reduced FEV1 (F  1, N  1, T1, and T2; p  0.04).
of ADAM33 was not only important in the development Linkage disequilibrium mapping of ADAM33 pointed to
of asthma but also in disease progression, possibly related functional SNPs lying between F  1 and B  1.
to enhanced airway remodeling. A further study by the Taken together, these studies support the notion that
same group investigated whether SNPs in ADAM33 could ADAM33 may be a gene involved in lung development
also predict an accelerated FEV1 decline at a population and further remodeling over a lifetime (Fig. 4.1). This may

41
Asthma and COPD: Basic Mechanisms and Clinical Management

then contribute to an accelerated loss of lung function and from gene expression studies and transcription factor
contribute as well to BHR. Given the associations with binding analysis on C-1112T strongly support a functional
dierent SNPs, ADAM33 may have dierential function role of this polymorphism in gene expression [101]. Genetic
inducing dierent phenotypes in men. variations in IL-13 have been associated with asthma and
related phenotypes in almost all studies that assess SNPs in
IL-13 (Table 4.1), and this is present in ethnically diverse
Genegene interaction: populations living in variable environmental circumstances
IL-13, IL-4, and IL-4R [5055, 5760, 6265, 67, 70, 7274, 102].
In the coding region of the IL-4Ralpha gene, at least
Il-13 and IL-4 are cytokines produced by Th2 cells that are 14 polymorphisms have been identied and for some of the
capable of inducing isotype class switching of B-cells to pro- more frequent genetic variations, functional data is available.
duce IgE. They also share a receptor component, IL-4R, SNP A148G alters an amino acid in the extracellular part of
which is an important factor in the development or expres- the receptor (I50V) which leads to increased IgE produc-
sion of atopy and asthma. The IL-13 receptor consists of one tion in B cells [102]. Polymorphisms T1432C and A1652G
IL-4R subunit and either a low-anity IL-13R1 or a lead to amino acid changes Ser478Pro and Gln551Arg in
high-anity IL-13R2 subunit. The complete receptor for the intracellular domain of the IL-4Ra chain, respectively.
IL-4 is composed of one IL-4R subunit and an IL-4R Dierent studies have assessed the eect of these polymor-
subunit, or IL-13 subunit (Fig. 4.2). IL-4 and IL-13 are phisms on atopic diseases [50, 56, 59, 61, 62, 64, 66, 68,
located on chromosome 5q and share the IL-4 receptor 72, 73, 103]. However, overall, the associations between
-chain, which is located at chromosome 16p12. IL-4Ralpha polymorphisms and the diagnosis of asthma as
In IL-13 seven frequent polymorphisms exist of well as serum IgE levels were only minor. In 2002, Howard
which at least three could be of functional relevance: et al. published a combined analysis of two polymorphisms
Polymorphism G2044A alters an amino acid in the protein in the IL-4/ IL-13 pathway [62]. In a longitudinal popula-
domain involved with receptor binding (Arg 130Gln) [71]. tion of Dutch adults with asthma, one polymorphism in the
This SNP and two other polymorphisms in the promoter promoter of IL-13 (C-1112T) and one in the IL-4Ra gene
(A-1512C and C-1112T) showed association with asthma leading to an amino acid change (Ser478Pro) were assessed.
and IgE regulation in dierent populations [54, 65]. Results The SNP in IL-13 (C-1112T) was previously found to be
associated with BHR in this population. The SNP in IL-4Ra
was associated with higher levels of IgE. As both traits are
associated with asthma the authors studied interaction of
ADAM33 these genes. When individuals with polymorphic alleles in
both locations were compared to individuals with wild-type
Lung function (FEV1)

Asthma alleles in both locations the risk for asthma increased vefold.
ADAM33
Also, the interaction between the polymorphism in
the coding region of IL-13 (G2044A) and the promoter
ADAM33 polymorphism C-589T in IL-4 has been studied [64]. The
ADAM33
IL-13 G2044A polymorphism and haplotypes consisting of
COPD IL-13 G2044A and IL-4 C-589T were associated with the
ADAM33 development of atopy and atopic dermatitis. As children in
this analysis were only followed up to the age of 24 months,
no information on asthma was available.
Age (years) Three polymorphisms in the IL-4 receptor alpha gene
(Arg551Glu, Ile50Val, and Pro478Ser) have been investigated
FIG. 4.1The phases of lung function growth and decline: growth, plateau
and decline phase. In all three phases ADAM33 may contribute to the
in combination with a promoter polymorphism in the IL-4
course of lung functions over a lifetime. gene (C-589T) [68]. The risk for asthma increased up to an

Type I IL-4 Type II IL-4 IL-13 receptor


receptor receptor

IL-4 IL-4
IL-13

Membrane

IL-13R IL-13R

IL-4R IL-4R IL-4R


C

FIG. 4.2 Interaction between IL4 and IL13 and their respective receptors, that have some similarities.

42
Genetics of Asthma and COPD 4
odds ratio (OR) of 1.97 (95% CI 1.073.71) in individuals directing the adaptive immune response. The CD14 gene
with the Arg allele at position 551 while the other two SNPs contains several SNPs, the most important one being the
in the IL-4Ra gene did not show any signicant eects. The CD14/-159 (also called CD14/-260). Functional genomic
combination of the IL-4Ralpha Arg allele with the IL-4 studies showed that monocytic cells with the T allele are
589T allele increased the OR to 3.70 (95% CI 1.07 transcriptionally more active [103].
12.78). This study extends the initial ndings by Howard in The initial study by Baldini et al. [104] demonstrated
the sense that a second combination of genes seems to inter- that the C-159T polymorphism was associated with elevated
act in the IL-4/ IL-13 pathway. In a similar British study, soluble CD14 levels, and reduced total serum IgE levels in
two polymorphisms in the IL-4Ra gene (Arg551Glu and children who were skin prick test positive to common aeroal-
Ile50Val, respectively) and two in the IL-4 gene (the highly lergens. Not all studies have been consistent however, rais-
linked SNPs C-589T and C-33T, respectively) were ana- ing the possibility that the level of environmental exposure
lyzed concomitantly. While transmission disequilibrium tests to endotoxin may alter the eect of CD14 polymorphisms
and haplotype analysis showed signicant associations with [105]. A number of recent studies have supported this notion.
asthma for both genes individually, the authors state that no Endotoxin. The hygiene hypothesis proposes that
interaction between the two genes was observed. However, microbial exposure during early life development reduces
no data and no information on how interaction was tested, is the development of asthma and allergic disease [106] and
provided [66]. has been the subject of many genetic association studies
Other researchers also failed to replicate interactions [107]. The timing, dose, and route of microbial exposures,
between polymorphisms in the IL-4/IL-13 pathway. Liu such as endotoxin, are likely to interact with genetic inu-
et al. investigated six polymorphisms in IL-4, IL-13, and ences, thus altering the response to these exposures [106].
IL-4Ra in almost 1000 children who were followed from Exposure to endotoxin is known to occur indoors from
birth. The eects of genetic variation in the IL-4/IL-13 contact with house dust. In the Barbados Asthma Genetics
pathway on specic and total serum IgE levels were ana- Study, subjects with low house dust endotoxin exposure,
lyzed [65]. The authors conrmed a role of IL-13 polymor- who had the CD14-159TT genotype had a reduced risk of
phisms in the regulation of total and specic IgE, but SNPs asthma whereas high exposure increased the risk of asthma
in IL-4 and IL4-Ra were only associated with specic IgE with this genotype [107]. Taken together, these studies pro-
responses in that study population. Although the interac- vide support for an endotoxin switch in which there is a
tion analysis is not shown, the authors state that no signi- dose-dependent response to endotoxin exposure for specic
cant interactions between polymorphisms in the three genes risk genotypes [108]. Exposure to endotoxin is also encoun-
were found. A further study on IL-4, IL-4Ra, IL-13, and tered in occupational settings such as farming. Adult farm-
IL-13Ra1 provided association of the IL-13 G2044A poly- ers with the CD14-159TT and -1691GG genotypes had
morphism with asthma in two populations, without signi- signicantly lower lung function and increased wheezing
cant interaction [53]. In contrast, recent studies by Kabesch compared with other genotypes, possibly due to increased
et al. [72] and Chan et al. [73] found signicant interactions soluble CD14 levels interacting with inhaled endotoxin
between the genes in the IL-4/IL-13 pathway. from the agricultural environment [103].
Dierences in observations may result from small Animal exposure. The type of microbial exposure
study population sizes and from characteristics of the popu- during immune system maturation may inuence the
lation under study, for example the dierences due to age, development of atopy and asthma. In children with the
gender, prevalence of atopy, high- and low-risk population CD14-159C allele who had regular contact with pets,
and so on. Thus the ndings need more study. However, it is serum IgE levels were higher than with the T allele [109].
shown that genegene interaction may contribute to asthma The opposite occurred in children with regular contact with
and atopy development. Analyses of genes in pathways that stable animals where the C allele was associated with lower
are relevant to atopy, asthma and or its subphenotypes like IgE levels. In another study, early life farm environment and
BHR need further attention. the CD14-159TT genotype combined to give the lowest
risk of nasal allergies and atopy [110].
Environmental tobacco smoke. Exposure to environ-
Geneenvironment interaction: CD14 mental tobacco smoke may increase the risk of asthma
in susceptible individuals. In a study of Puerto Rican
Innate immunity genes provide the interface between the and Mexican families, people with asthma who had the
immune system and microbial products. Many microbes CD14  1437GG or GC genotypes and exposure to envi-
have specic pattern molecules on their surfaces and these ronmental tobacco smoke had a mean forced expiratory
molecules interact with pattern-recognition receptors. volume in 1 s that was lower by 8.6% of that predicted as
CD14 is such a receptor. CD14 is part of the receptor com- compared with GG or GC subjects that were not exposed
plex for lipopolysaccharide (LPS, endotoxin) together with to environmental tobacco smoke [111]. In addition, people
toll-like receptors (TLR) 2 and 4. CD14 does not have a with asthma with the CD14-159TT genotype and expo-
transmembrane domain and thus does not signal itself but sure to environmental tobacco smoke had lower serum IgE
contributes to the anity of the interaction between the levels. The mechanism for this interaction could involve
microbial products and TLRs by formation of a receptor exposure to endotoxin found in cigarettes. Sex dierences
complex. Downstream eects include the upregulation of may also exist in response to tobacco smoke. Girls whose
accessory molecules and release of cytokines, such as IL-10 mothers had smoked during pregnancy or whose parents
and IL-12. These cytokines are potentially important in had asthma had lower mean soluble CD14 levels [112].

43
Asthma and COPD: Basic Mechanisms and Clinical Management

Asthma pharmacogenetics: The treatment-related changes in lung function. Israel et al.


beta2-adrenergic receptor [123] matched asthmatic individuals homozygous Arg/Arg
(n 37) to those Gly/Gly (n 41), by level of FEV1. The
The therapeutic response to beta2-agonists is heterogeneous genotype-stratied individuals were then randomized in a
in asthmatic subjects [113], a nding suggested to be due double-blind, cross-over study of regularly scheduled qid
in part to genetic variation in the beta2-adrenergic receptor albuterol therapy versus placebo over two 16-week periods.
gene (ADRB2). A number of ADRB2 polymorphisms have Again, those with the Arg/Arg genotype had lower morn-
been described [114], with the greatest attention devoted to ing PEF versus placebo (10 l/min, p 0.02), while those
the SNPs causing amino acid substitutions at positions 16 with Gly/Gly had higher PEF (14 l/min, p 0.02). The dif-
and 27, namely the Gly16Arg and the Gln27Glu polymor- ference between Arg/Arg and Gly/Gly genotypes was sig-
phisms [115, 116]. Many of the early studies on the acute nicant for morning PEF (24 l/min, p 0.0003), evening
bronchodilator response to a beta-agonist diered substan- PEF, FEV1, morning symptom score, and need for rescue
tially from one another with respect to study design, type of medication.
agonist utilized, and primary outcome assessed [117, 118]. Further studies have focused on asthma exacerbations
Not surprisingly, there was marked inconsistency in results as an outcome. With regular use of both short- and long-
between trials. Subsequently, larger studies have demon- acting beta-agonists, presence of at least one Gly16 allele is
strated that bronchodilator responses were higher and more protective against exacerbations [124]. Moreover, in a meta-
rapid among Arg16 homozygotes as compared to Gly16 analysis evaluating long-acting beta-agonist usage, subjects
homozygotes and heterozygotes [119, 120]. with at least one Arg allele demonstrated signicant decre-
The second phenotypic outcome evaluated has been ments in PC20 when compared to placebo, suggesting that
the potential for downregulation of beta-agonist receptor the downregulation of the receptor accompanying tachyph-
responsivity (tachyphylaxis) with the chronic administration ylaxis may result in decreased bronchoprotection [125].
of beta-agonists in association with ADRB2 genetic vari- Several studies have assessed the eects of long-
ants. In a key study, 255 asthmatics of mild severity were acting beta-agonists [126128]. Wechsler et al. showed
randomized to either regular (180 g QID) or as-needed decreased responses to salmeterol in Arg/Arg subjects com-
albuterol use and were assessed over a 16-week period for pared with Gly/Gly subjects [126]. In the Salmeterol or
evidence of tachyphylaxis and clinical deterioration (as Corticosteroids (SOCS) trial, morning peak ow worsened
measured by fall in AM peak expiratory ow rate (PEF)). in Arg/Arg asthmatic subjects (n 12) who were treated
No dierence in PEF variation was observed between treat- with salmeterol alone after inhaled corticosteroids (ICS)
ment groups [121]. However, Arg16 homozygotes sig- withdrawal when compared with subjects who received
nicantly decreased their pre-albuterol PEF with regular placebo; no decrease in morning peak ow was observed
utilization of albuterol therapy, compared to both Arg16 in Gly/Gly subjects (n 13). In the Salmeterol and/or
homozygotes receiving as-needed albuterol and Gly16 Inhaled Corticosteroid (SLIC) trial, Arg/Arg (n 8) asth-
homozygotes in either treatment group [121]. The dier- matic subjects did not show a sustained improvement in
ence in evening PEF between these groups was 31.6  10.2 lung function as compared with Gly/Gly (n 22) subjects
l/min comparing Arg16 homozygous regular users ver- on salmeterol, regardless of whether subjects were admin-
sus Gly16 homozygous regular users (p 0.002) and istered concomitant ICS. As these studies were all of small
31.1  13.0 l/min versus the Arg16 homozygous as needed size that may confound the outcome of the analyses, larger
group (p 0.02) [122]. Similar dierences in morning PEF studies are required to rmly establish whether polymor-
were noted (Fig. 4.3). phisms in the ADRB2 gene do aect the benecial clinical
2AR desensitization was further evaluated in a eects of long-acting beta2-antagonists (LABA) treatment
prospective, genotype-stratied study of Arg16Gly on when added to inhaled steroids. The size of the study popu-
lation is of importance, particularly given the variability of
individual responses to pharmacotherapy both between sub-
jects and within subjects on a day-to-day basis.
10 Finally, previous studies have illustrated that rela-
Arg/Arg-as needed
Gly/Gly-regular tively few ABRB2 haplotypes account for the majority of
5
the haplotypic diversity of this gene, and that the frequency
AM PEF (l /min)

0 of common haplotypes diers between population groups


[115, 129]. An eect of ADRB2 haplotype on acute bron-
5
chodilator responses to albuterol has been demonstrated in
10 some studies [128] but not in others [115, 130].
15
Arg/Arg-regular Studies on ADRB2 provide evidence that the gene
is likely to be associated with bronchodilator response but
20 that genetic prediction of this response may vary by eth-
25 nic group. Additionally, individuals homozygous for Arg16
0 5 10 15 20 demonstrate signicant 2AR desensitization and these
Run out individuals (approximately 15% of population) are at risk of
Weeks after randomization
clinical deterioration with the regular use of beta-agonists.
FIG. 4.3 Change in morning PEF (Peak Expiratory Flow) with beta-agonist Future studies have to assess whether this is still the case if
(albuterol) treatment, according to ADRB2 genetic variants. patients are being treated with ICs.

44
Genetics of Asthma and COPD 4
most rapid FEV1 decline and 308 subjects who had no meas-
COPD GENETIC ASSOCIATION STUDIES urable FEV1 decline over 5 years. EPHX1 haplotypes were
associated with rate of FEV1 decline, and this association
Biological candidate gene: Microsomal was more signicant among individuals who reported a fam-
ily history of COPD potentially related to other COPD
epoxide hydrolase genetic risk factors, which act additively with EPHX1 or
which interact with EPHX1 to increase COPD risk.
Microsomal epoxide hydrolase is a xenobiotic enzyme that Hersh and colleagues studied a total of eight EPHX1
detoxies highly reactive epoxides, which are created by cig- SNPs, which included the two widely studied nonsynony-
arette smoking. Thus, variation in the activity of this enzyme mous SNPs above, in a family-based study and a casecon-
has been hypothesized to contribute to variable COPD trol study [81]. The family-based Boston Early-Onset
susceptibility. In an early COPD genetic association study, COPD Study subjects included 127 extended pedigrees
Smith and Harrison studied two genetic variants in the (949 total subjects) ascertained through a proband with
EPHX1 gene [75], one of which had been reported to cause severe, early-onset COPD; the casecontrol study included
reduced activity of this xenobiotic enzyme (Tyr113His) 304 severe COPD subjects from the National Emphysema
and the other which had been reported to cause increased Treatment Trial (NETT) and 441 control smokers from the
enzyme activity (His139Arg). They analyzed two small case Normative Aging Study. None of the EPHX1 SNPs were
groups that included 68 subjects with spirometrically proven associated with quantitative or qualitative airway obstruc-
COPD and 94 patients with both pathologically proven tion phenotypes in the early-onset COPD families under an
emphysema and lung cancer. Their control group of 203 additive model. However, the Arg139 allele showed modest
blood donors was not phenotyped. Both their COPD and evidence for association to COPD in the casecontrol study.
emphysema/lung cancer case groups had signicantly higher Overall, there is reasonable but not uniformly con-
frequencies of homozygosity for the His113 slow allele sistent evidence for association between EPHX1 SNPs and
associated with reduced EPHX1 enzyme activity. Somewhat COPD. The small sample sizes of many of these studies
paradoxically, a higher frequency of the Arg139 fast allele could contribute to inconsistent replication. A further expla-
associated with increased EPHX1 enzyme activity was also nation might be dierences in ethnicities; however, another
found in the COPD cases compared to controls. potential contribution to these inconsistent results is phe-
In a study of 180 former poison gas factor workers notypic heterogeneity within the COPD cases. COPD
in Japan, followed to determine the impact of these toxic includes both emphysema and airway disease in varying
exposures on the development of lung disease, Yoshikawa proportions between dierent subjects, and emphysema dis-
and colleagues compared the distributions of the Tyr113His tribution also varies widely between subjects. DeMeo and
and His139Arg variants in 40 subjects with COPD colleagues studied emphysema distribution in 282 of the
(FEV1  70% predicted) and the remaining 140 subjects 304 NETT Genetics Ancillary Study participants studied
[76]. No signicant dierences were observed in allele fre- by Hersh and colleagues who had chest CT scans with den-
quencies between these groups. However, when they sub- sitometric and radiologist assessment of emphysema sever-
divided their 40 COPD cases into 20 mild (FEV1  60% ity and distribution [131]. The EPHX1 His139Arg SNP
predicted) and 20 moderate/severe (FEV1  60% pre- was signicantly associated with emphysema distribution
dicted) subjects, a higher frequency of the slow His113 assessed by densitometry (p 0.005) and by radiologist
allele was observed in the more severely aected subjects. scoring (p 0.01). To determine whether utilizing a more
Thus, they speculated that EPHX1 variants were associated homogeneous set of COPD cases would improve the abil-
with COPD severity rather than susceptibility. ity to detect genetic association, the association results using
Two other small casecontrol genetic association all NETT COPD cases were compared to the results using
studies, performed in Asian populations and published in only 171 upper lobe predominant emphysema cases; the
2000, found no association between the Tyr113His and same set of 441 control subjects was used for both com-
His139Arg variants and COPD [78, 80]. In a subsequent parisons. Despite including a smaller number of COPD
study of 184 COPD cases and 212 control smokers from cases, the upper lobe predominant emphysema group asso-
Taiwan, the genotype frequencies for the Tyr113His and ciation analysis indicated that the Arg139 fast allele was
His139Arg SNPs did not dier between the cases and more protective (OR 0.60 with p 0.005) compared to
controls [41]. However, using the genotypes at both posi- the association analysis using all COPD cases (OR 0.73
tions to assign two functional EPHX1 categories (slow/very with p 0.02). These results suggest that phenotypic het-
slow versus normal/fast), did lead to a signicant dierence erogeneity could contribute to the inconsistent replication
between cases and controls. Moreover, homozygosity for of EPHX1 (and other COPD candidate gene SNPs) asso-
the His113 allele was more prevalent in severe versus mild ciations with COPD; more comprehensive phenotyping of
COPD cases. More recently, Brogger and colleagues stud- COPD cases, including chest CT scans, should be consid-
ied 244 subjects meeting spirometric criteria for COPD ered for future COPD genetic studies.
and 248 control subjects [77]. They found that the His113
variant was associated with COPD.
Sandford and colleagues studied the impact of haplo- Another xenobiotic enzyme gene: GSTP1
types formed by the two widely studied EPHX1 SNPs on
rate of decline in FEV1 among continuing smokers in the Like EPHX1, glutathione S-transferase P1 (GSTP1)
Lung Health Study [79]. They selected 283 subjects with the detoxies oxygen radicals produced by cigarette smoke; it

45
Asthma and COPD: Basic Mechanisms and Clinical Management

has been extensively studied as a COPD candidate gene. colleagues genotyped the Arg213Gly variant in 230 COPD
Ishii and colleagues studied two nonsynonymous SNPs in cases and 210 control smokers [87]. Importantly, as the Gly213
GSTP1 in 53 COPD cases and 50 control subjects from variant was hypothesized to confer resistance to COPD among
Japan [81]. A higher frequency of Ile105 homozygotes smokers, their control subjects had normal spirometry with a
at the Ile105Val SNP was observed in COPD cases (79% heavy smoking history (mean pack-years 42). The allele fre-
versus 52%); some evidence suggests that the Ile105 variant quency of Gly213 was only 1% in the COPD cases but it was
confers reduced functional activity of the GSTP1 enzyme 5% in the control smokers (p 0.02). Carriers of at least one
[132]. In a Korean population of 89 COPD cases and 94 Gly213 allele were signicantly more common among controls
smoking controls, Yim and colleagues found no association than cases (p 0.005).
of the Ile105Val SNP with COPD [84]. In the Lung Health In the Copenhagen City Heart Study, Juul and col-
Study, He and his colleagues compared 544 subjects with leagues studied the Arg213Gly variant in 9258 Danish sub-
the highest baseline FEV1 values (mean FEV1 91.8% jects [88]. They conrmed the marked eect of this variant
predicted) to 554 subjects with the lowest baseline FEV1 on EC-SOD plasma levels, with mean values of 142 ng/ml
values (mean FEV1 62.6% predicted); all of these subjects in Arg213 homozygotes, 1278 ng/ml in Arg213/Gly213
had COPD based on reduced FEV1/FVC ratio [85]. They heterozygotes, and 4147 ng/ml in Gly213 homozygotes.
observed a higher frequency of Val105 homozygotes among In a multivariate model adjusting for gender, age, smoking,
the low lung function group (13.2% versus 9.3%), as well as and occupational dust exposure, smokers who were hetero-
a faster rate of FEV1 decline in high lung function subjects zygous (Arg213/Gly213) had substantially lower risk for
who were Val105 homozygotes. COPD than Arg213 homozygotes (OR 0.4, with 95% CI
There are multiple potential explanations for the incon- 0.20.8). Among nonsmokers, no protective eect of the
sistent results of these previous studies, including population Gly213 variant for COPD was observed. Only two Gly213
dierences (ethnicity, COPD status), failure to analyze the homozygous subjects were identied in the entire cohort.
actual functional variant in GSTP1, and small samples in sev- This conrms the potentially protective eect of the Gly213
eral of the studies. However, it is also possible that genegene allele among smokers, and it emphasizes the utility of large
interactions need to be considered to identify key COPD sample sizes especially when studying relatively uncom-
susceptibility genes. Studies of combinations of GSTP1 vari- mon genetic variants.
ants with other potential susceptibility genes have also been
performed. Calikoglu and colleagues did nd a higher fre-
quency of Ile105 homozygotes in a male Turkish population
of 149 COPD cases (61%) compared to 150 control subjects TGFB1: Convergence of biological and
(38%) [86]. They also examined the impact of including vari- positional candidate gene approaches
ants in GSTT1 and GSTM1 in combination with GSTP1
and found a markedly increased risk of COPD when a com- Transforming growth factor beta 1 (TGFB1) is a cytokine
bination of variants in these three genes was considered. In that acts as a central regulator of the inammatory response;
addition to EPHX1, Cheng and colleagues also studied the thus, it is a logical biological candidate gene for COPD.
GSTP1 Ile105Val variant in their set of 184 COPD cases A potentially functional variant has been identied at
and 212 control subjects from Taiwan [41]. Although the codon 10, which changes a leucine to a proline (Leu10Pro);
Ile105Val SNP was not associated with COPD when ana- individuals that carry at least one proline allele have higher
lyzed individually, the combination of at least one EPHX1 TGFB1 mRNA in peripheral blood mononuclear cells and
slow allele (His113), homozygosity for the GSTM1 Null higher serum TGFB1 protein levels [134]. Wu and col-
allele, and homozygosity for the Ile105 allele was signicantly leagues genotyped this nonsynonymous SNP in Caucasian
more common in COPD cases (36%) versus controls (8.5%). subjects from New Zealand. They included 165 COPD
Formal tests of interaction in large samples will be required cases and two control groups 76 control smokers and 140
to replicate these ndings and to determine whether these unphenotyped blood donors [89]. The Pro10 allele was less
results represent the combination of susceptibility alleles act- common in COPD cases (33%) than in either the blood
ing independently or signicant genegene interactions. donor controls (45%) or smoking controls (45%).
Celedon and colleagues identied TGFB1 as a posi-
tional candidate gene on chromosome 19q after performing
linkage analysis in 72 extended pedigrees (585 individuals)
Association with a relatively uncommon ascertained through severe, early-onset COPD probands [91].
allele: SOD3 The initial evidence for linkage of FEV1 to 19q was mod-
est (LOD score 1.40). However, genotyping additional
Although genetic association studies typically analyze common short tandem repeat markers to increase the information
genetic variants with allele frequencies above 10%, it is quite available for linkage analysis, as well as performing a strati-
likely that less common variants contribute to the susceptibility, ed analysis in smokers only (to identify genomic regions
and resistance, to complex diseases like COPD. Extracellular likely inuenced by gene-by-smoking interactions), led to
superoxide dismutase (EC-SOD or SOD3) detoxies oxy- more substantial evidence for linkage (LOD score 3.30).
gen radicals by scavenging superoxide anions. A variant in this TGFB1 is located within the linkage region, and ve SNPs
gene, Arg213Gly, has been shown to have a functional eect were genotyped in both Boston Early-Onset COPD Study
on the processing of the EC-SOD protein, leading to substan- pedigrees for family-based association analysis and in a set of
tially elevated plasma levels of the protein [133]. Young and 304 COPD cases and 441 smoking control subjects. Three

46
Genetics of Asthma and COPD 4
SNPs were signicantly associated with COPD phenotypes were associated with airow obstruction phenotypes in the
in each population, and one SNP in the promoter region of Boston Early-Onset COPD families; a SNP-by-smoking
TGFB1 (rs2241718) replicated in both study populations. interaction term was included in those analyses. Five of
The Leu10Pro variant was only signicantly associated in the these 18 SNPs demonstrated replicated associations in the
casecontrol analysis, but a lower Pro10 allele frequency was casecontrol cohort. Although Chappell and colleagues
noted in COPD cases indicating the same directionality of wrote a Letter to the Editor indicating that they could not
eect as in the study by Wu and colleagues. replicate these associations in their casecontrol cohort [96],
Following these initially supportive studies using the Zhu and colleagues recently reported their analyses of 25
biological and positional candidate gene approaches, further SERPINE2 SNPs in both a family-based cohort of 1910
replication eorts of TGFB1 in COPD susceptibility have subjects and a casecontrol cohort from Norway includ-
had mixed results. In a small study comparing 84 COPD ing 973 COPD cases and 956 control smokers [97]. The
cases and 97 control subjects from China, signicant dif- family-based association analysis demonstrated association
ferences in both allele and genotype frequencies were noted of ve SNPs to COPD, with p values as low as 0.002. The
for two TGFB1 promoter SNPs [93]. However, association casecontrol analysis only found one SNP with p  0.05
analysis of the Leu10Pro SNP and two promoter SNPs for COPD aection status; however, ve SNPs were associ-
in 102 COPD cases and 159 control smokers from Korea ated with FEV1/FVC in COPD cases; these were the same
showed no evidence for association [90]. Furthermore, in ve SNPs associated with COPD in the family-based asso-
a comparison of 283 continuing smokers with rapid FEV1 ciation analysis. Thus, reasonable evidence for replication
decline versus 307 continuing smokers with slow FEV1 has been found, supporting the utility of future studies of
decline in the Lung Health Study, Ogawa and colleagues SERPINE2 association and function to conrm whether it
found no association between three TGFB1 SNPs (includ- is a valid COPD susceptibility gene.
ing the Leu10Pro SNP) and FEV1 decline [92]. van Diemen
and colleagues studied three TGFB1 SNPs including one
promoter SNP (rs1800469, C-509T), one nonsynonymous PERSPECTIVES ON GENETICS
SNP (rs1982073, Leu10Pro), and one 3
untranslated region
SNP (rs6957) in a general population sample of 1390 indi- OF ASTHMA AND COPD
viduals in the Netherlands who were followed longitudinally
for 25 years [94]. Although they found no association of As demonstrated in this chapter, the research on genetics of
TGFB1 SNPs with FEV1 decline, rs6957 was signicantly asthma and COPD has become a promising new eld. The
more common in 188 subjects meeting criteria for GOLD main goal of the industries and the research institutes is to
Stage II COPD than among the remainder of the cohort nd the genes that increase susceptibility to develop asthma
(p 0.001). Additional studies of TGFB1 in COPD will and COPD.
be required, including larger numbers of SNPs in larger Both in asthma and in COPD the heterogene-
study populations, to denitively conrm or refute the role ity of the diseases with complex hereditary traits and many
of TGFB1 genetic variants in COPD susceptibility. (sub)phenotypes are obstacles to nd the right genetic infor-
mation easily. Although a rapidly increasing number of genes
are being implicated in asthma and COPD pathogenesis,
SERPINE2: Integrating genomics and the functional variants in these genes have not been deni-
genetics in COPD tively identied; this is a major area requiring investigation.
In the pathogenesis of asthma and COPD it is reasonable to
Although genetic linkage studies can point to chromo- suspect that the interactions between multiple genes and
somal regions that are likely to include susceptibility genes multiple environmental triggers are important. This will
for a complex disease, such regions typically contain many require collaboration between many researchers combining
genes. In addition to the approaches of selecting a biologi- their cohorts that have been carefully phenotyped for asthma
cally plausible positional candidate gene (as for TGFB1) and COPD. By combining large cohorts with systematic
or dense genotyping of SNP markers (not yet reported for analyses of environmental risk factors, comprehensive assess-
COPD) within linkage regions, assessment of gene expres- ment of genetic polymorphisms (including genome-wide
sion can point to promising candidate genes that would SNP genotyping), and genetic analysis with advanced statis-
not have been suspected based on our current knowledge tical techniques, we will better understand the genetic deter-
of disease pathobiology. DeMeo and colleagues integrated minants and heterogeneity of asthma and COPD. Hopefully
gene expression microarray results from two data sets one this will lead to new treatments, intervention strategies, and
data set analyzed mouse lung development and the other nally prevention of asthma and COPD.
data set compared gene expression in human lung tissue
for the genes located within their linkage region to airway
obstruction on chromosome 2q [95]. Based on these gene
expression results, SERPINE2 (Serpin Peptidase Inhibitor,
ACKNOWLEDGEMENTS
Clade E, Member 2) was selected as a candidate gene, and
48 SNPs were genotyped in a family-based cohort (949 Research on asthma and COPD in Groningen is supported
individuals from 127 Boston Early-Onset COPD Study by the Netherlands Asthma Foundation, ZonMW and
pedigrees) and a casecontrol cohort (304 COPD cases KNAW. Dr. Silverman was supported by NIH grants R01
and 441 control smokers). Eighteen SERPINE2 SNPs HL075478 and HL68926.

47
Asthma and COPD: Basic Mechanisms and Clinical Management

References 19. Engle LJ, Simpson CL, Landers JE. Using high-throughput SNP
technologies to study cancer. Oncogene 25: 1594601, 2006.
20. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO,
1. Holberg CJ, Elston RC, Halonen M, Wright AL, Taussig LM, Morgan Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J.
WJ, Martinez FD. Segregation analysis of physician-diagnosed asthma HTRA1 promoter polymorphism in wet age-related macular degen-
in hispanic and non-hispanic white families. Am J Respir Crit Care Med eration. Science 314: 98992, 2006.
154: 14450, 1996. 21. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P,
2. Laurell CB, Eriksson S. The electrophoretic 1-globulin pattern of serum Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G,
in 1-antitrypsin deciency. Scand J Clin Lab Invest 15: 13240, 1963. Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI,
3. DeMeo DL, Sandhaus RA, Barker AF, Brantly ML, Eden E, Balding DJ, Meyre D, Polychronakos C, Froguel P. A genome-wide
McElvaney NG, Rennard S, Burchard EG, Stocks JM, Stoller JK, association study identies novel risk loci for type 2 diabetes. Nature
Strange C, Turino GM, Campbell EJ, Silverman EK. Determinants 445: 88185, 2007.
of airow obstruction in severe alpha 1-antitrypsin deciency. Thorax 22. Moatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S,
62: 80613. 2007. Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B,
4. Lewitter FI, Tager IB, McGue M, Tishler PV, Speizer FE. Genetic Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland
and environmental determinants of level of pulmonary function. Am J SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM,
Epidemiol 120: 51829, 1984. Cookson WO. Genetic variants regulating ORMDL3 expression con-
5. Silverman EK, Chapman HA, Drazen JM, Weiss ST, Rosner B, tribute to the risk of childhood asthma. Nature 448: 47073, 2007.
Campbell EJ, ODonnell WJ, Reilly JJ, Ginns L, Mentzer S, Wain J, 23. Lander E, Kruglyak L. Genetic dissection of complex traits: Guidelines
Speizer FE. Genetic epidemiology of severe, early-onset chronic for interpreting and reporting linkage results. Nat Genet 11: 24147, 1995.
obstructive pulmonary disease: Risk to relatives for airow obstruction 24. Celedon JC, Raby B, Weiss ST et al. (eds). Asthma genetics. In:
and chronic bronchitis. Am J Respir Crit Care Med 157: 177078, 1998. Silverman EK, Shapiro SD, Lomas DA, and Weiss ST. Respiratory
6. DeMeo DL, Carey VJ, Chapman HA, Reilly JJ, Ginns LC, Speizer Genetics, pp. 21996. London: Hodder Arnold, 2005.
FE, Weiss ST, Silverman EK. Familial aggregation of FEF(25-75) and 25. Van Eerdewegh P et al. Association of the ADAM33 gene with asthma
FEF(25-75)/FVC in families with severe, early onset COPD. Thorax and bronchial hyperresponsiveness. Nature 418: 42630, 2002.
59: 396400, 2004. 26. Allen M et al. Positional cloning of a novel gene inuencing asthma
7. McCloskey SC, Patel BD, Hinchlie SJ, Reid ED, Wareham NJ, from chromosome 2q14. Nat Genet 35: 25863, 2003.
Lomas DA. Siblings of patients with severe chronic obstructive pulmo- 27. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J, Holt R,
nary disease have a signicant risk of airow obstruction. Am J Respir Edser P, Bhattacharyya S, Dunham A, Adcock IM, Pulleyn L,
Crit Care Med 164: 141924, 2001. Barnes PJ, Harper JI, Abecasis G, Cardon L, White M, Burton J,
8. Pennisi E. Human genome. Finally, the book of life and instructions Matthews L, Mott R, Ross M, Cox R, Moatt MF, Cookson WO.
for navigating it. Science 288: 23047, 2000. Positional cloning of a quantitative trait locus on chromosome 13q14
9. Pennisi E. Genetics. Working the (gene count) numbers: Finally, a rm that inuences immunoglobulin E levels and asthma. Nat Genet 34:
answer?. Science 316: 1113, 2007. 18186, 2003.
10. Schmidt-Weber CB. Gene expression proling in allergy and asthma. 28. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P,
Chem Immunol Allergy 91: 18894, 2006. Makela S, Rehn M, Pirskanen A, Rautanen A, Zucchelli M, Gullsten H,
11. Nomura I, Gao B, Boguniewicz M, Darst MA, Travers JB, Leung DY. Leino M, Alenius H, Petays T, Haahtela T, Laitinen A, Laprise C,
Distinct patterns of gene expression in the skin lesions of atopic Hudson TJ, Laitinen LA, Kere J. Characterization of a common sus-
dermatitis and psoriasis: A gene microarray analysis. J Allergy Clin ceptibility locus for asthma-related traits. Science 304: 3004, 2004.
Immunol 112: 1195202, 2003. 29. Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z, Billstrand C,
12. Chavanas S, Garner C, Bodemer C, Ali M, Teillac DH, Wilkinson J, Kuldanek S, Donfack J, Kogut P, Patel NM, Goodenbour J, Howard T,
Bonafe JL, Paradisi M, Kelsell DP, Ansai S, Mitsuhashi Y, Larregue M, Wolf R, Koppelman GH, White SR, Parry R, Postma DS, Meyers D,
Leigh IM, Harper JI, Taieb A, Prost Y, Cardon LR, Hovnanian A. Bleecker ER, Hunt JS, Solway J, Ober C. Fine mapping and positional
Localization of the Netherton syndrome gene to chromosome 5q32, candidate studies identify HLA-G as an asthma susceptibility gene on
by linkage analysis and homozygosity mapping. Am J Hum Genet 66: chromosome 6p21. Am J Hum Genet 76: 34957, 2005.
91421, 2000. 30. Noguchi E, Yokouchi Y, Zhang J, Shibuya K, Shibuya A, Bannai M,
13. Walley AJ, Chavanas S, Moatt MF, Esnouf RM, Ubhi B, Lawrence R, Tokunaga K, Doi H, Tamari M, Shimizu M, Shirakawa T, Shibasaki M,
Wong K, Abecasis GR, Jones EY, Harper JI, Hovnanian A, Cookson Ichikawa K, Arinami T. Positional identication of an asthma suscep-
WO. Gene polymorphism in Netherton and common atopic disease. tibility gene on human chromosome 5q33. Am J Respir Crit Care Med
Nat Genet 29: 17578, 2001. 172: 18388, 2005.
14. Kabesch M, Carr D, Weiland SK, von Mutius E. Association between 31. Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A,
polymorphisms in serine protease inhibitor, kazal type 5 and asthma Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ,
phenotypes in a large German population sample. Clin Exp Allergy 34: Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST.
34045, 2004. Genomewide linkage analysis of quantitative spirometric phenotypes
15. Jongepier H, Koppelman GH, Nolte IM, Bruinenberg M, in severe early-onset chronic obstructive pulmonary disease. Am J Hum
Bleecker ER, Meyers DA, te Meerman GJ, Postma DS. Polymorphisms Gen 70: 122939, 2002.
in SPINK5 are not associated with asthma in a Dutch population. 32. DeMeo DL, Celedon JC, Lange C, Reilly JJ, Chapman HA, Sylvia JS,
J Allergy Clin Immunol 115: 48692, 2005. Speizer FE, Weiss ST, Silverman EK. Genome-wide linkage of forced
16. Kelleher CM, Silverman EK, Broekelmann T, Litonjua AA, Hernandez mid-expiratory ow in chronic obstructive pulmonary disease. Am J
M, Sylvia JS, Stoler J, Reilly JJ, Chapman HA, Speizer FE, Weiss ST, Respir Crit Care Med 170: 1294301, 2004.
Mecham RP, Raby BA. A functional mutation in the terminal exon of 33. Malhotra A, Peier AP, Ryujin DT, Elsner T, Kanner RE, Leppert MF,
elastin in severe, early-onset chronic obstructive pulmonary disease. Hasstedt SJ. Further evidence for the role of genes on chromosome 2
Am J Respir Cell Mol Biol 33: 35562, 2005. and chromosome 5 in the inheritance of pulmonary function. Am J
17. Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Respir Crit Care Med 168: 55661, 2003.
Donnelly P. A haplotype map of the human genome. Nature 437: 34. Postma DS, Meyers DA, Jongepier H, Howard TD, Koppelman GH,
1299320, 2005. Bleecker ER. Genomewide screen for pulmonary function in 200 families
18. Syvanen AC. Toward genome-wide SNP genotyping. Nat Genet ascertained for asthma. Am J Respir Crit Care Med 172: 44652, 2005.
37(Suppl): S510, 2005.

48
Genetics of Asthma and COPD 4
35. Ober C, Hoffjan S. Asthma genetics 2006: The long and winding road 53. Heinzmann A et al. Genetic variants of IL-13 signalling and human
to gene discovery. Genes Immun 7: 95100, 2006. asthma and atopy. Hum Mol Genet 9: 54959, 2000.
36. Hoffjan S, Nicolae D, Ober C. Association studies for asthma and atopic 54. Graves PE, Kabesch M, Halonen M, Holberg CJ, Baldini M, Fritzsch
diseases: A comprehensive review of the literature. Respir Res 4: 14, 2003. C, Weiland SK, Erickson RP, von Mutius E, Martinez FD. A cluster
37. Kere J, Laitinen T. Positionally cloned susceptibility genes in allergy of seven tightly linked polymorphisms in the IL-13 gene is associ-
and asthma. Curr Opin Immunol 16: 68994, 2004. ated with total serum IgE levels in three populations of white children.
38. Lind DL, Choudhry S, Ung N, Ziv E, Avila PC, Salari K, Ha C, J Allergy Clin Immunol 105: 50613, 2000.
Lovins EG, Coyle NE, Nazario S, Casal J, Torres A, Rodriguez- 55. Liu X, Nickel R, Beyer K, Wahn U, Ehrlich E, Freidho LR, Bjorksten B,
Santana JR, Matallana H, Lilly CM, Salas J, Selman M, Boushey HA, Beaty TH, Huang SK. An IL13 coding region variant is associated with
Weiss ST, Chapela R, Ford JG, Rodriguez-Cintron W, Silverman EK, a high total serum IgE level and atopic dermatitis in the German mul-
Sheppard D, Kwok PY, Gonzalez Burchard E. ADAM33 is not associ- ticenter atopy study (MAS-90). J Allergy Clin Immunol 106: 16770,
ated with asthma in Puerto Rican or Mexican populations. Am J Respir 2000.
Crit Care Med 168: 131216, 2003. 56. Takabayashi A, Ihara K, Sasaki Y, Suzuki Y, Nishima S, Izuhara K,
39. Howard TD, Postma DS, Jongepier H, Moore WC, Koppelman GH, Hamasaki N, Hara T. Childhood atopic asthma: Positive association
Zheng SL, Xu J, Bleecker ER, Meyers DA. Association of a disintegrin with a polymorphism of IL-4 receptor alpha gene but not with that of
and metalloprotease 33 (ADAM33) gene with asthma in ethnically IL-4 promoter or Fc epsilon receptor I beta gene. Exp Clin Immunogenet
diverse populations. J Allergy Clin Immunol 112: 71722, 2003. 17: 6370, 2000.
40. Raby BA, Silverman EK, Kwiatkowski DJ, Lange C, Lazarus R, 57. Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin
Weiss ST. ADAM33 polymorphisms and phenotype associations in JM. Atopy and asthma: Genetic variants of IL-4 and IL-13 signalling.
childhood asthma. J Allergy Clin Immunol 113: 107178, 2004. Immunol Today 21: 6064, 2000.
41. Cheng SL, Yu CJ, Chen CJ, Yang PC. Genetic polymorphism of 58. Noguchi E, Nukaga-Nishio Y, Jian Z, Yokouchi Y, Kamioka M,
epoxide hydrolase and glutathione S-transferase in COPD. Eur Respir J Yamakawa-Kobayashi K, Hamaguchi H, Matsui A, Shibasaki M,
23: 81824, 2004. Arinami T. Haplotypes of the 5 region of the IL-4 gene and SNPs in
42. Wang P, Liu QJ, Li JS, Li HC, Wei CH, Guo CH, Gong YQ. Lack of the intergene sequence between the IL-4 and IL-13 genes are associ-
association between ADAM33 gene and asthma in a Chinese popula- ated with atopic asthma. Hum Immunol 62: 125157, 2001.
tion. Int J Immunogenet 33: 3036, 2006. 59. Leung TF, Tang NL, Chan IH, Li AM, Ha G, Lam CW. A polymor-
43. Lee JH, Park HS, Park SW, Jang AS, Uh ST, Rhim T, Park CS, Hong phism in the coding region of interleukin-13 gene is associated with
SJ, Holgate ST, Holloway JW, Shin HD. ADAM33 polymorphism: atopy but not asthma in Chinese children. Clin Exp Allergy 31: 151521,
Association with bronchial hyper-responsiveness in Korean asthmatics. 2001.
Clin Exp Allergy 34: 86065, 2004. 60. Howard TD, Whittaker PA, Zaiman AL, Koppelman GH, Xu J, Hanley
44. Schedel M, Depner M, Schoen C, Weiland SK, Vogelberg C, MT, Meyers DA, Postma DS, Bleecker ER. Identication and associa-
Niggemann B, Lau S, Illig T, Klopp N, Wahn U, von Mutius E, Nickel R, tion of polymorphisms in the interleukin-13 gene with asthma and atopy
Kabesch M. The role of polymorphisms in ADAM33, a disintegrin in a Dutch population. Am J Respir Cell Mol Biol 25: 37784, 2001.
and metalloprotease 33, in childhood asthma and lung function in two 61. Wjst M, Kruse S, Illig T, Deichmann K. Asthma and IL-4 receptor
German populations. Respir Res 7: 91, 2006. alpha gene variants. Eur J Immunogenet 29: 26368, 2002.
45. Jongepier H, Boezen HM, Dijkstra A, Howard TD, Vonk JM, 62. Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, Meyers
Koppelman GH, Zheng SL, Meyers DA, Bleecker ER, Postma DS. DA, Bleecker ER. Genegene interaction in asthma: IL4RA and IL13
Polymorphisms of the ADAM33 gene are associated with accelerated in a Dutch population with asthma. Am J Hum Genet 70: 23036, 2002.
lung function decline in asthma. Clin Exp Allergy 34: 75760, 2004. 63. DeMeo DL, Lange C, Silverman EK, Senter JM, Drazen JM,
46. Werner M, Herbon N, Gohlke H, Altmuller J, Knapp M, Heinrich J, Barth MJ, Laird N, Weiss ST. Univariate and multivariate family-based
Wjst M. Asthma is associated with single-nucleotide polymorphisms association analysis of the IL- 13 ARG130GLN polymorphism in the
in ADAM33. Clin Exp Allergy 34: 2631, 2004. Childhood Asthma Management program. Genet Epidem 23: 33548,
47. Simpson A, Maniatis N, Jury F, Cakebread JA, Lowe LA, Holgate 2002.
ST, Woodcock A, Ollier WE, Collins A, Custovic A, Holloway JW, 64. He JQ, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC,
John SL. Polymorphisms in a disintegrin and metalloprotease 33 Manfreda J, Watson WT, Sandford AJ. Genetic variants of the IL13
(ADAM33) predict impaired early-life lung function. Am J Respir Crit and IL4 genes and atopic diseases in at-risk children. Genes Immun 4:
Care Med 172: 5560, 2005. 38589, 2003.
48. Blakey J, Halapi E, Bjornsdottir US, Wheatley A, Kristinsson S, 65. Liu X, Beaty TH, Deindl P, Huang SK, Lau S, Sommerfeld C, Fallin
Upmanyu R, Stefansson K, Hakonarson H, Hall IP. Contribution of MD, Kao WH, Wahn U, Nickel R. Associations between total serum
ADAM33 polymorphisms to the population risk of asthma. Thorax 60: IgE levels and the 6 potentially functional variants within the genes
27476, 2005. IL4, IL13, and IL4RA in German children: The German Multicenter
49. Noguchi E, Ohtsuki Y, Tokunaga K, Yamaoka-Sageshima M, Ichikawa Atopy Study. J Allergy Clin Immunol 112: 38288, 2003.
K, Aoki T, Shibasaki M, Arinami T. ADAM33 polymorphisms are 66. Beghe B, Barton S, Rorke S, Peng Q, Sayers I, Gaunt T, Keith TP,
associated with asthma susceptibility in a Japanese population. Clin Clough JB, Holgate ST, Holloway JW. Polymorphisms in the inter-
Exp Allergy 36: 6028, 2006. leukin-4 and interleukin-4 receptor alpha chain genes confer susceptibil-
50. Deichmann KA, Heinzmann A, Forster J, Dischinger S, Mehl C, ity to asthma and atopy in a Caucasian population. Clin Exp Allergy 33:
Brueggenolte E, Hildebrandt F, Moseler M, Kuehr J. Linkage and 111117, 2003.
allelic association of atopy and markers anking the IL4-receptor gene. 67. Hummelshoj T, Bodtger U, Datta P, Malling HJ, Oturai A, Poulsen LK,
Clin Exp Allergy 28: 15155, 1998. Ryder LP, Sorensen PS, Svejgaard E, Svejgaard A. Association between
51. Celedon JC, Soto-Quiros ME, Palmer LJ, Senter J, Mosley J, Silverman an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet
EK, Weiss ST. Lack of association between a polymorphism in the 30: 35559, 2003.
interleukin-13 gene and total serum immunoglobulin E level among 68. Lee SG, Kim BS, Kim JH, Lee SY, Choi SO, Shim JY, Hong TJ,
nuclear families in Costa Rica. Clin Exp Allergy 32: 38790, 2002. Hong SJ. Genegene interaction between interleukin-4 and inter-
52. van der Pouw Kraan TC, van Veen A, Boeije LC, van Tuyl SA, de Groot leukin-4 receptor alpha in Korean children with asthma. Clin Exp
ER, Stapel SO, Bakker A, Verweij CL, Aarden LA, van der Zee JS. Allergy 34: 12028, 2004.
An IL-13 promoter polymorphism associated with increased risk of 69. Hoffjan S, Ostrovnaja I, Nicolae D, Newman DL, Nicolae R,
allergic asthma. Genes Immun 1: 6165, 1999. Gangnon R, Steiner L, Walker K, Reynolds R, Greene D, Mirel D,

49
Asthma and COPD: Basic Mechanisms and Clinical Management

Gern JE, Lemanske RF Jr., Ober C. Genetic variation in immu- 87. Young RP, Hopkins R, Black PN, Eddy C, Wu L, Gamble GD, Mills
noregulatory pathways and atopic phenotypes in infancy. J Allergy Clin GD, Garrett JE, Eaton TE, Rees MI. Functional variants of antioxi-
Immunol 113: 51118, 2004. dant genes in smokers with COPD and in those with normal lung
70. Nieters A, Linseisen J, Becker N. Association of polymorphisms in function. Thorax 61: 39499, 2006.
Th1, Th2 cytokine genes with hayfever and atopy in a subsample of 88. Juul K, Tybjaerg-Hansen A, M S, Lange P, Nordestgaard BG.
EPIC-Heidelberg. Clin Exp Allergy 34: 34653, 2004. Genetically increased antioxidant protection and decreased chronic
71. Vladich FD, Brazille SM, Stern D, Peck ML, Ghittoni R, Vercelli D. obstructive pulmonary disease. Am J Respir Crit Care Med, 173: 858
IL-13 R130Q, a common variant associated with allergy and asthma, 64, 2006.
enhances eector mechanisms essential for human allergic inamma- 89. Wu L, Chau J, Young RP, Pokorny V, Mills GD, Hopkins R, McLean L,
tion. J Clin Invest 115: 74754, 2005. Black PN. Transforming growth factor-beta1 genotype and susceptibility
72. Kabesch M, Schedel M, Carr D, Woitsch B, Fritzsch C, Weiland SK, von to chronic obstructive pulmonary disease. Thorax 59: 12629, 2004.
Mutius E. IL-4/IL-13 pathway genetics strongly inuence serum IgE 90. Yoon HI, Silverman EK, Lee HW, Yoo CG, Lee CT, Chung HS,
levels and childhood asthma. J Allergy Clin Immunol 117: 26974, 2006. Kim YW, Han SK, Shim YS, Yim JJ. Lack of association between
73. Chan IH, Leung TF, Tang NL, Li CY, Sung YM, Wong GW, Wong COPD and transforming growth factor-b1 (TGFB1) genetic poly-
CK, Lam CW. Genegene interactions for asthma and plasma total morphisms in Koreans. Int J Tuberc Lung Dis, 10: 50409, 2006.
IgE concentration in Chinese children. J Allergy Clin Immunol 117: 91. Celedon JC, Lange C, Raby BA, Litonjua AA, Palmer LJ, DeMeo
12733, 2006. DL, Reilly JJ, Kwiatkowski DJ, Chapman HA, Laird N, Sylvia JS,
74. Hunninghake GM, Soto-Quiros ME, Avila L, Su J, Murphy A, Hernandez M, Speizer FE, Weiss ST, Silverman EK. The transform-
Demeo DL, Ly NP, Liang C, Sylvia JS, Klanderman BJ, Lange C, ing growth factor-beta1 (TGFB1) gene is associated with chronic
Raby BA, Silverman EK, Celedon JC. Polymorphisms in IL13, total obstructive pulmonary disease (COPD). Hum Mol Genet 13: 164956,
IgE, eosinophilia, and asthma exacerbations in childhood. J Allergy Clin 2004.
Immunol 120: 8490, 2007. 92. Ogawa E, Ruan J, Connett JE, Anthonisen NR, Pare PD, Sandford AJ.
75. Smith CAD, Harrison DJ. Association between polymorphism in gene Transforming growth factor-beta1 polymorphisms, airway responsive-
for microsomal epoxide hydrolase and susceptibility to emphysema. The ness and lung function decline in smokers. Respir Med 101: 93843,
Lancet 350: 63033, 1997. 2007.
76. Yoshikawa M, Hiyama K, Ishioka S, Maeda H, Maeda A, Yamakido 93. Su ZG, Wen FQ, Feng YL, Xiao M, Wu XL. Transforming growth
M. Microsomal epoxide hydrolase genotypes and chronic obstructive factor-beta1 gene polymorphisms associated with chronic obstruc-
pulmonary disease in Japanese. Int J Mol Med 5: 4953, 2000. tive pulmonary disease in Chinese population. Acta Pharmacol Sin 26:
77. Brogger J, Steen VM, Eiken HG, Gulsvik A, Bakke P. Genetic asso- 71420, 2005.
ciation between COPD and polymorphisms in TNF, ADRB2 and 94. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Nolte IM,
EPHX1. Eur Respir J 27: 68288, 2006. Boezen HM. Decorin and TGF-beta1 polymorphisms and develop-
78. Yim JJ, Park GY, Lee CT, Kim YW, Han SK, Shim YS, Yoo CG. ment of COPD in a general population. Respir Res 7: 89, 2006.
Genetic susceptibility to chronic obstructive pulmonary disease in 95. DeMeo D, Mariani TJ, Lange C, Srisuma SS, Litonjua AA,
Koreans: Combined analysis of polymorphic genotypes for microsomal Celedon JC, Lake SL, Reilly JJ, Chapman HA, Mecham BH, Haley
epoxide hydrolase and glutathione S-transferase M1 and T1. Thorax 55: KJ, Sylvia JS, Sparrow D, Spira A, Beane J, Pinto-Plata V, Speizer FE,
12125, 2000. Shapiro SD, Weiss ST, Silverman EK. The SERPINE2 gene is asso-
79. Sandford AJ, Chagani T, Weir TD, Connett JE, Anthonisen NR, Pare ciated with chronic obstructive pulmonary disease. Am J Hum Genet
PD. Susceptibility genes for rapid decline of lung function in the Lung 178: 25364, 2006.
Health Study. Am J Respir Crit Care Med 163: 46973, 2001. 96. Chappell S, Daly L, Morgan K, Baranes TG, Roca J, Rabinovich R,
80. Takeyabu K, Yamaguchi E, Suzuki I, Nishimura M, Hizawa N, Millar A, Donnelly SC, Keatings V, MacNee W, Stolk J, Hiemstra PS,
Kamakami Y. Gene polymorphism for microsomal epoxide hydrolase Miniati M, Monti S, OConnor CM, Kalsheker N. The SERPINE2
and susceptibility to emphysema in a Japanese population. Eur Respir J gene and chronic obstructive pulmonary disease. Am J Hum Genet 79:
15: 89194, 2000. 18486, 2006, author reply 1867.
81. Hersh CP, Demeo DL, Lange C, Litonjua AA, Reilly JJ, Kwiatkowski 97. Zhu G, Warren L, Aponte J, Gulsvik A, Bakke P, ICGN
D, Laird N, Sylvia JS, Sparrow D, Speizer FE, Weiss ST, Silverman Investigators, Anderson WH, Lomas DA, Silverman EK, Pillai SG.
EK. Attempted replication of reported chronic obstructive pulmo- The SERPINE2 gene is associated with chronic obstructive pulmo-
nary disease candidate gene associations. Am J Respir Cell Mol Biol 33: nary disease in two large populations. Am J Respir Crit Care Med 176:
7178, 2005. 16773, 2007.
82. Cheng L, Enomoto T, Hirota T, Shimizu M, Takahashi N, Akahoshi 98. Dijkstra A, Vonk JM, Jongepier H, Koppelman GH, Schouten JP,
M, Matsuda A, Dake Y, Doi S, Enomoto K, Yamasaki A, Fukuda S, ten Hacken NH, Timens W, Postma DS. Lung function decline in
Mao XQ, Hopkin JM, Tamari M, Shirakawa T. Polymorphisms in asthma: Association with inhaled corticosteroids, smoking and sex.
ADAM33 are associated with allergic rhinitis due to Japanese cedar Thorax 61: 10510, 2006.
pollen. Clin Exp Allergy 34: 1192201, 2004. 99. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP,
83. Ishii T, Matsuse T, Teramoto S, Matsui H, Miyao M, Hosoi T, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms
Takahashi H, Fukuchi Y, Ouchi Y. Glutathione S-transferase P1 and lung function decline in the general population. Am J Respir Crit
(GSTP1) polymorphism in patients with chronic obstructive pulmo- Care Med 172: 32933, 2005.
nary disease. Thorax 54: 69396, 1999. 100. Gosman MM, Boezen HM, van Diemen CC, Snoeck-Stroband JB,
84. Yim JJ, Yoo CG, Lee CT, Kim YW, Han SK, Shim YS. Lack of associ- Lapperre TS, Hiemstra PS, Ten Hacken NH, Stolk J, Postma DS.
ation between glutathione S-transferase P1 polymorphism and COPD A disintegrin and metalloprotease 33 and chronic obstructive pulmo-
in Koreans. Lung 180: 11925, 2002. nary disease pathophysiology. Thorax 62: 24247, 2007.
85. He JQ, Connett JE, Anthonisen NR, Pare PD, Sandford AJ. 101. Vercelli D. Genetics of IL-13 and functional relevance of IL-13 vari-
Glutathione S-transferase variants and their interaction with smoking ants. Curr Opin Allergy Clin Immunol 2: 38993, 2002.
on lung function. Am J Respir Crit Care Med 170: 38894, 2004. 102. Kruse S, Braun S, Deichmann KA. Distinct signal transduction proc-
86. Calikoglu M, Tamer L, Ates Aras N, Karakas S, Ercan B. The esses by IL-4 and IL-13 and inuences from the Q551R variant of
association between polymorphic genotypes of glutathione S-trans- the human IL-4 receptor alpha chain. Respir Res 3: 24, 2002.
ferases and COPD in the Turkish population. Biochem Genet 44: 103. LeVan TD, Von Essen S, Romberger DJ, Lambert GP,
30719, 2006. Martinez FD, Vasquez MM, Merchant JA. Polymorphisms in the

50
Genetics of Asthma and COPD 4
CD14 gene associated with pulmonary function in farmers. Am J 121. Drazen JM, Israel E, Boushey HA, Chinchilli VM, Fahy JV, Fish JE,
Respir Crit Care Med 171: 77379, 2005. Lazarus SC, Lemanske RF, Martin RJ, Peters SP, Sorkness C, Szeer
104. Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, SJ. Comparison of regularly scheduled with as-needed use of albuterol
Martinez FD. A Polymorphism* in the 5 anking region of the CD14 in mild asthma. Asthma Clinical Research Network. N Engl J Med 33:
gene is associated with circulating soluble CD14 levels and with total 84147, 1996.
serum immunoglobulin E. Am J Respir Cell Mol Biol 20: 97683, 1999. 122. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM,
105. Martinez FD. Geneenvironment interactions in asthma and aller- Chinchilli VM, Cooper DM, Fahy JV, Fish JE, Ford JG, Kraft M,
gies: A new paradigm to understand disease causation. Immunol Kunselman S, Lazarus SC, Lemanske RF, Martin RJ, McLean DE,
Allergy Clin North Am 25: 70921, 2005. Peters SP, Silverman EK, Sorkness CA, Szeer SJ, Weiss ST, Yandava
106. Liu AH, Leung DY. Renaissance of the hygiene hypothesis. J Allergy CN. The eect of polymorphisms of the beta(2)-adrenergic receptor
Clin Immunol 117: 106366, 2006. on the response to regular use of albuterol in asthma. Am J Respir Crit
107. Zambelli-Weiner A, Ehrlich E, Stockton ML, Grant AV, Zhang S, 3are Med 162: 7580, 2000.
Levett PN, Beaty TH, Barnes KC. Evaluation of the CD14/-260 122. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig
polymorphism and house dust endotoxin exposure in the Barbados TJ, Deykin A, Fagan JK, Fahy JV, Fish J, Kraft M, Kunselman SJ,
Asthma Genetics Study. J Allergy Clin Immunol 115: 12039, 2005. Lazarus SC, Lemanske RF Jr., Liggett SB, Martin RJ, Mitra N,
108. Yang IA, Fong KM, Holgate ST, Holloway JW. The role of Toll- Peters SP, Silverman E, Sorkness CA, Szeer SJ, Wechsler ME,
like receptors and related receptors of the innate immune system in Weiss ST, Drazen JM. Use of regularly scheduled albuterol treatment
asthma. Curr Opin Allergy Clin Immunol 6: 2328, 2006. in asthma: Genotype-stratied, randomised, placebo-controlled cross-
109. Eder W, Klimecki W, Yu L, von Mutius E, Riedler J, Braun- over trial. The Lancet 364: 150512, 2004.
Fahrlander C, Nowak D, Martinez FD. Opposite eects of CD 14/- 124. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town
260 on serum IgE levels in children raised in dierent environments. GI. Asthma exacerbations during long term beta agonist use: Inuence
J Allergy Clin Immunol 116: 6017, 2005. of beta(2) adrenoceptor polymorphism. Thorax 55: 76267, 2000.
110. Leynaert B, Guilloud-Bataille M, Soussan D, Benessiano J, Guenegou 125. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ. The arginine-16
A, Pin I, Neukirch F. Association between farm exposure and atopy, beta2-adrenoceptor polymorphism predisposes to bronchoprotective
according to the CD14 C-159T polymorphism. J Allergy Clin subsensitivity in patients treated with formoterol and salmeterol. Br J
Immunol 118: 65865, 2006. Clin Pharmacol 57: 6875, 2004.
111. Choudhry S, Avila PC, Nazario S, Ung N, Kho J, Rodriguez-Santana 126. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr., Boushey HA,
JR, Casal J, Tsai HJ, Torres A, Ziv E, Toscano M, Sylvia JS, Alioto M, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, DiMango E,
Salazar M, Gomez I, Fagan JK, Salas J, Lilly C, Matallana H, Castro Kraft M, Leone F, Martin RJ, Peters SP, Szeer SJ, Liu W, Israel E.
RA, Selman M, Weiss ST, Ford JG, Drazen JM, Rodriguez-Cintron beta-Adrenergic receptor polymorphisms and response to salmeterol.
W, Chapela R, Silverman EK, Burchard EG. CD14 tobacco gene- Am J Respir Crit Care Med 173: 51926, 2006.
environment interaction modies asthma severity and immunoglobu- 127. Bleecker ER, Yancey SW, Baitinger LA, Edwards LD, Klotsman M,
lin E levels in Latinos with asthma. Am J Respir Crit Care Med 172: Anderson WH, Dorinsky PM. Salmeterol response is not aected by
17382, 2005. beta2-adrenergic receptor genotype in subjects with persistent asthma.
112. Lodrup Carlsen KC, Lovik M, Granum B, Mowinckel P, Carlsen J Allergy Clin Immunol 118: 80916, 2006.
KH. Soluble CD14 at 2 yr of age: Gender-related eects of tobacco 128. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The
smoke exposure, recurrent infections and atopic diseases. Pediatr Salmeterol Multicenter Asthma Research Trial: A comparison of
Allergy Immunol 17: 30412, 2006. usual pharmacotherapy for asthma or usual pharmacotherapy plus sal-
113. Sin DD, Man J, Sharpe H, Gan WQ, Man SF. Pharmacological man- meterol. Chest 129: 1526, 2006.
agement to reduce exacerbations in adults with asthma: A systematic 129. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS,
review and meta-analysis. JAMA 292: 36776, 2004. Nandabalan K, Arnold K, Ruano G, Liggett SB. Complex promoter
114. Hawkins GA, Tantisira K, Meyers DA, Ampleford EJ, Moore WC, and coding region beta 2-adrenergic receptor haplotypes alter recep-
Klanderman B, Liggett SB, Peters SP, Weiss ST, Bleecker ER. Sequence, tor expression and predict in vivo responsiveness. Proc Natl Acad Sci
haplotype, and association analysis of ADRbeta2 in a multiethnic asthma USA 97: 1048388, 2000.
casecontrol study. Am J Respir Crit Care Med 174: 11019, 2006. 130. Taylor DR, Epton MJ, Kennedy MA, Smith AD, Iles S, Miller AL,
115. Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. Meta-analysis Littlejohn MD, Cowan JO, Hewitt T, Swanney MP, Brassett KP,
of the association of beta2-adrenergic receptor polymorphisms with Herbison GP. Bronchodilator response in relation to beta2-adreno-
asthma phenotypes. J Allergy Clin Immunol 115: 96372, 2005. ceptor haplotype in patients with asthma. Am J Respir Crit Care Med
116. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymor- 172: 7003, 2005.
phisms of the human beta-2 adrenergic receptor impart distinct agonist- 131. DeMeo DL, Hersh CP, Homan EA, Litonjua AA, Lazarus R,
promoted regulatory properties. Biochemistry 33: 941419, 1994. Sparrow D, Benditt JO, Criner GJ, Make B, Martinez FJ, Scanlon PD,
117. Ohe M, Munakata M, Hizawa N, Itoh A, Doi I, Yamaguchi E, Sciurba FC, Utz JP, Reilly JJ, Silverman EK. Genetic determinants of
Homma Y, Kawakami Y. Beta 2 adrenergic receptor gene restriction emphysema distribution in the National Emphysema Treatment Trial.
fragment length polymorphism and bronchial asthma. Thorax 50: Am J Respir Crit Care Med 176: 4248, 2007.
35359, 1995. 132. Sundberg K, Johansson AS, Stenberg G, Widersten M, Seidel A,
118. Aziz I, McFarlane LC, Lipworth BJ. Comparative trough eects Mannervik B, Jernstrom B. Dierences in the catalytic eciencies of
of formoterol and salmeterol on lymphocyte beta2-adrenoceptor allelic variants of glutathione transferase P1-1 towards carcinogenic
regulation and bronchodilatation. Eur J Clin Pharmacol 55: 43136, diol epoxides of polycyclic aromatic hydrocarbons. Carcinogenesis 19:
1999. 43336, 1998.
119. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. 133. Olsen DA, Petersen SV, Oury TD, Valnickova Z, Thogersen IB,
Association between genetic polymorphisms of the beta-2 adrenocep- Kristensen T, Bowler RP, Crapo JD, Enghild JJ. The intracellular pro-
tor and response to albuterol in children with and without a history of teolytic processing of extracellular superoxide dismutase (EC-SOD)
wheezing. J Clin Invest 100: 318488, 1997. is a two-step event. J Biol Chem 279: 2215257, 2004.
120. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self TH, 134. Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE,
Johnson JA. Impact of genetic polymorphisms of the beta2-adren- August P. Transforming growth factor-beta 1 hyperexpression in
ergic receptor on albuterol bronchodilator pharmacodynamics. Clin African-American hypertensives: A novel mediator of hypertension
Pharmacol Ther 65: 51925, 1999. and/or target organ damage. Proc Natl Acad Sci USA 97: 347984, 2000.

51
Physiology and 2
PART

Pathology of
Asthma and COPD
Pulmonary Physiology
5
CHAPTER

INTRODUCTION volume which distinguish these airway disor-


ders from restrictive processes of the respiratory Charles G. Irvin
system that reduce lung volumes. Lung volumes
Asthma is an inammatory disease principally have important bearing on the degree of dis- Department of Medicine and
of the small airways but current understanding is ease since increases in the residual volume (RV) Physiology, University of Vermont
that all the airways are involved [1]. The physi- occur relatively early even with mild airway dis- College of Medicine, Burlington, VT, USA
ological manifestations of lung inammation are ease whereas increases in the total lung capacity
reversible airow limitation and airow limita- (TLC) are usually an indication of more severe
tion that uctuates widely with time; asthma or long-standing disease (Fig. 5.1) [46].
can also result in persistent loss of lung function. The most useful lung volumes and capaci-
In contrast, airow obstruction in patients with ties to measure are those that assess the physical
chronic obstructive pulmonary disease (COPD) limits of the lung and chest wall and dene the
presents with both reversible and irreversible air- extremes of the vital capacity (VC); TLC and
ow limitation, the latter linked to loss of static RV. The volume in the lung at end expiratory
elastic recoil due in part to the destruction of the position, the functional residual capacity (FRC),
architecture of the lung. The airow limitation is important because of the inuence that lung
of COPD has much less temporal or periodic volume has on airway caliber and in turn on
variation over the short term but patients with airow resistance during eupnea. TLC, FRC,
COPD usually exhibit steady consistent losses of and RV are boundary conditions of respiration
lung function over a period of years. In reality the and accordingly provide the most information
clinical presentation of both COPD and asthma about the capacity and function of the respira-
is often quite variable and the pathophysiologi- tory system [6]. Assessing the changes in these
cal data alone do not allow a denitive diagnosis. lung volumes to evaluate disease severity and
This confusing presentation of patients with fea- response to therapy allows one to distinguish
tures of both asthma and COPD is in keeping between obstructive lung disease and restrictive
with the overlap observed in the epidemiology lung disease (Table 5.1) [8, 9].
of these diseases [2, 3]. The focus of this chap- Obstructive lung diseases such as chronic
ter is on the pathophysiological presentation of bronchitis, asthma, and emphysema all result
COPD and asthma and the features that distin- in increases in lung volume. An increase in
guish each disease as well as the similarities. This TLC usually represents more chronic, severe
chapter will also examine the physiological proc- disease, and in the case of COPD it is related
esses that characterize airways disease. to remodeling of the chest wall leading to the
so-called barrel chest. The increase in TLC
may have another more important role; that is
the preservation of forced vital capacity (FVC)
LUNG VOLUMES AND ELASTIC RECOIL in face of a rise in RV that would then result
in more pronounced falls in FEV1 if the rise in
TLC had not ameliorated the fall in FVC [4,
Lung volumes and capacities 7]. The increase in TLC in parallel with each
increase in RV can occur until the chest wall
In diseases of the airway such as asthma and reaches some structural limit which probably
COPD there are characteristic increases in varies from person to person [7, 10] and acutely
55
Asthma and COPD: Basic Mechanisms and Clinical Management

(B) Structural limit


TLC
(A)

VC
IRV IC

Volume
VC
FRC
Volume

TV
FRC
RV
ERV

RV

Time RV Mild Moderate Severe


Disease severity

FIG. 5.1 (A) The figure presents a trace of volume displacement as a function of time during quiet breathing followed by a maximal inspiration to TLC, the
subject then exhales the VC until no more air exits the lung. The volume of gas remaining in the lung at this point is RV. FRC is the volume left in the lung at
the end of each normal breath. Expiratory reserve (ERV) and inspiratory reserve volume (IRV) are as noted. The inspiratory capacity (IC) is the volume of air
inspired from FRC to TLC and is sometimes used as a surrogate for TLC. The three boundary conditions TLC, RV, FRC provide the most useful information as to
the functioning of the lung (see text). (B) The figure present the changes in lung volumes and capacities that occur with increased airway disease severity as
during an asthma attack or during the progression of COPD. The first (and last) change is usually an increase in RV (mild) as airway closure increases the RV
continues to rise but FVC does not fall if the TLC rises in concert [4, 7]. However, at some point in the disease process (severe) or depending on the flexibility
of the chest wall a structural limit is reached where the TLC cannot increase further. At this point the further rise in RV results in a fall in VC, FVC, and FEV1
(see text).

TABLE 5.1 Boundaries of lung volume and physical determinants. balance of elastic forces of the respiratory system (see
below). Increases in FRC observed in airways disease may
Volume or represent a loss of recoil of the lung as occurs in emphysema
capacity TLC (%) Determinants or an increase in outward recoil of the chest wall. In the case
of the latter, the inspiratory respiratory muscle in eect reset
TLC: total lung Respiratory muscle function
the equilibrium point of the respiratory system to a higher
capacity Structural limits of chest wall distortion
volume such as occurs during an asthma attack [6, 20]. For
Compliance of chest wall and lung
patients with asthma or COPD, the FRC increases by sev-
FRC: function 50 Compliance of chest wall and lung eral mechanisms including persistent activity of the respira-
residual capacity Expiratory time constants tory muscles [20], increased expiratory time constants [20],
Respiratory muscle activity or alterations in recoil. Severe increases in FRC occur in
patients with more severe forms of COPD because all these
RV: residual 2030 Airway closure mechanisms occur in concert (Fig. 5.2).
volume Adequate expiratory effort
Children (18 years): chest wall
compliance
Elastic recoil
Note: TLC (%): total lung capacity for normal persons.
Pressurevolume (PV) relationships are used to quantita-
tively display the elastic recoil of the components of the res-
during an exacerbation of disease (Fig. 5.1B). The cause piratory system: the chest wall and the lungs. Elastic recoil
of the increase in TLC is unknown but the possibilities is very important in a number of respects. First, the strength
include either a loss of an inhibitory reex that activates of the chest wall muscle when coupled to the elastic recoil of
the muscles of the chest wall as TLC is reduced or sim- the chest wall and lungs serve to determine the static lung
ple structural overdistension [1012]. For patients with volumes, specically the maximal excursion of the chest wall
COPD it would appear that the increase in TLC may as assessed by TLC and RV [6]. Second, the elastic recoil
also be due to remodeling of the chest wall and is com- as inuenced by changes in lung volume, alters intrapulmo-
monly observed in X-ray or CT images. Assessing changes nary airway caliber [1315, 21, 22]. Thirdly, elastic recoil is
in FRC is of particular importance because resting lung the most important load to smooth muscle contraction as
volume has such an important bearing on airway caliber changes in lung volumes have a profound eect on ASM
and airway smooth muscle (ASM) contractility [1319]. performance [18, 22]. Lastly, elastic recoil is the major driv-
Determination of FRC provides a reasonable alternative ing force for eort-independent maximal airow, inuencing
to the placement of an esophageal balloon to measure the peak ow and in particular FEV1 [23, 24].

56
Pulmonary Physiology 5
125 B Chest volume increases or decreases the airway caliber increases
wall or decreases [1315]. Since, the contraction of ASM is
A
dependent upon muscle ber length and constitutes the
100 load against which ASM must contract, lung volume sets
Lung
the starting load. The observation explains why at low lung
(% Predicted TLC)

volumes the response to an inhaled bronchoconstricting


75 FRC A  B agent is enhanced [16, 18, 19]. Hyperination diminishes
Volume

luminal narrowing caused by ASM activation as shown by


FRC A or B
animal [16, 17] or human studies [18, 19].
50 FRC

25
DETERMINANTS OF AIRWAY CALIBER

0 10 20 30 The size of an intrapulmonary airway lumen at any given


Pressure (cmH2O) lung volume (e.g. FRC) is generally thought to depend on:
(1) contents of the lumen (such as mucous plugs or liquid
FIG. 5.2 Pressurevolume (PV) relationships in a normal subject (heavy accumulation), (2) the structure of the airway both inter-
solid lines), asthmatic patient (chestwall shifts to B) and in a patient with nal and external to the smooth muscle, (3) activation state
emphysema (where the lung PV shift to A and chest wall to B: A  B). or bronchomotor tone of the airways smooth muscle, (4)
The heavy solid line to the left is the PV curve of the chest wall showing compliance or stiness of the airway wall, and (5) tether-
outward recoil up until 66% of TLC and the line to the right is the PV curve
ing forces of the attached alveolar wall or lung volume.
of the lung. For the normal person the equilibrium point (FRC) where
the outward recoil is equal but opposite to the inward recoil occurs at
Transmural pressure (Ptm), which is the pressure inside
about 50% of the TLC. However, for the patient with loss of recoil of the minus pressure outside of the airway, represents the sum-
lung (dashed line A) or chest (dashed line B) FRC rises because the inward mation of forces working to open or close the airway and is
recoil of the lung is less or the chest is more and a new equilibrium (FRC resisted by the structure (or compliance) of the airway wall.
A or B) is reached. However, when both the chest wall (B) and lung PV (A) In both asthma and COPD there is a considerable change
relationship change (both dashed lines) the FRC is increased further (FRC referred to as remodeling of these structural components of
A  B). the airway wall (Fig. 5.3).

Elastic recoil is diminished in all patients with Contents of the lumen


emphysema whereas patients with asthma or the bronchitic
form of COPD exhibit, on average, more normal recoil The biological processes that lead to obstructive lung disease
[2527]. A caveat is that the loss of static elastic recoil in leave the airway lumen lled with liquid, cells, and mucus;
asthmatic patients has been reported by several work- this accumulation is even more marked during acute exac-
ers [2729]. In asthma the loss in elastic recoil can occur erbations [35]. Indeed, this pathologic feature may be the
acutely [30], and can be reversed with bronchodilator treat- most physiologically signicant as obstruction of the airway
ment [28, 31]. Unlike emphysema where the loss of elas- causes much of the mismatch of ventilation to perfusion
tic recoil is thought to be due to microscopic destruction of and in turn results in hypoxemia (see below). Moreover
parenchyma [32], these more acute losses in elastic recoil in removal of such an obstruction is anything but straight-
some patients with asthma may relate to alterations in sur- forward as the contents change from being serous to more
face tension due to extravasation of plasma proteins from mucoid in nature. Acutely lumenal obstructions appear in
the inammation or as a result of airway luminal brin for- the peripheral branches of the dependent portions of the
mation within the airway lumen [33]. trachealbronchial tree [36, 37]. These pathological changes
Determination of FRC coupled with an assessment in the distal lung are associated with 10-fold increase in
of the chest wall (e.g. visual inspection) allows one to assess peripheral resistance [38, 39] that increases further with
the likely position of the lung PV relationship without the disease severity [4042]. Yet even with this 10-fold increase
issues associated with placement of an esophageal balloon. in peripheral resistance in the mild asthmatic, spirometry
For example, nding a low FRC in a patient that was not can still be within normal limits.
overweight or obese would indicate a restrictive process;
whereas an increase in measured FRC in a patient with nor-
mal appearing chest wall is suggestive of either persistent Structure of the airway wall
activity of the inspiratory muscles (especially if the patient
has labored breathing) or a loss of inward elastic recoil of Inammation of the airway wall characterizes all forms of
the lung or chest wall [6, 8]. obstructive airway disease. Structural alterations include
Elastic recoil has a profound eect on airway caliber. increased extracellular deposits of the extracellular matrix
As lung volume increases there is outward pull on intrapul- that include bronectin, collagen, vitronectin, and a host
monary airways since these airways are embedded in the of other components [43]. The apparent thickening of the
alveolar matrix of the parenchyma [34]. Hence, as lung basement membrane below the airway epithelium is due

57
Asthma and COPD: Basic Mechanisms and Clinical Management

(A) Normal Airways disease

1 plugging
2 folds
BM
6 3 liquid (B) Airway disease Normal
5
ASM
4 4 BM
5 ASM

ium 6 breaks
el
ith
Ep 7 Pel
Pel
1
7 8 thickening
Pbr
2
Palv 3 8

thickness wall stiffness

ASM contractility uncoupling parallel load ASM

series load ASM series load ASM

shortening, velocity barrier function

clearance

FIG. 5.3 (A) A schematic representation of the cross-section of an airway in a normal person (left-hand side of A) and a patient with obstructive airways
disease (right-hand side of A). The changes that occur during airway remodeling in obstructive lung disease that could either cause airway narrowing and
airway hyperresponsiveness or prevent airway hyperresponsiveness are presented. In asthma and COPD several factors are operational but the relationship
of these structural changes to lung function is anything but clear. The mechanisms that cause or prevent airway narrowing are several and include: (1) Debris
plugging of airway lumen, (2) decreased number of folds, (3) liquid in luminal folds of epithelium, (4) thickness of the basement membrane, (5) increased
in contractility and/or size of ASM, (6) breaks in the alveolar tethers, (7) loss of elastic recoil, and (8) thickening of airway wall. Pel: elastic recoil forces; Palv:
alveolar pressure; Pbr: pressure in the lumen of the bronchiole; Transmural pressure: the difference in Pbr Palv; ASM: airway smooth muscle. (B) Balance of
forces favoring airway narrowing or airway opening.

to type I and III collagen deposition and is observed even Compliance of the airway wall
in mild disease [44]. ASM is also increased both in volume
(hypertrophy) and in number (hyperplasia) [43]. The func- The structural components of the airway wall represent the
tional consequence of remodeling of the airway is uncertain; load to smooth muscle shortening, thus an increase in com-
indeed, there is little proof that there is a functional conse- pliance would amplify ASM contraction and a decrease in
quence. Arguments have been made that airway remodeling compliance would be expected to antagonize ASM shorten-
can both promote and protect the size of airway lumen [45] ing. Cartilage, an important structural element of the airway
(Fig. 5.3B). wall, would serve to protect the airway lumen and has been
shown to soften with disease [43, 48], an eect thought to
be due to inammatory mediators and the release of metal-
Activation state of the ASM loprotineases. Folding or buckling of the mucosa has been
speculated to either prevent airway narrowing or enhance
Bronchomotor tone has two consequences: rst, depending airway luminal narrowing by changing wall compliance
on the compliance of the airway wall, smooth muscle tone [46, 49]. In this situation as the wall is compressed by ASM
narrows airways and reduces airow but, secondly, smooth contraction, the layer internal to the ASM folds or buck-
muscle tone also stiens the airway wall as it contracts. les up. The folds reinforce each other which serve to prevent
A decrease of airway wall compliance would serve to pre- further narrowing with an apparent increased load to the
vent further collapse [45, 46]. This is best appreciated when ASM. However, if the folds are few in number [49] and/or
ASM is activated at low lung volumes. Several studies have interstices of the folds become lled with liquid because of
shown that when methacholine is inhaled in the supine the small radius of curvature of an individual fold and the
posture, compared to the upright posture, more severe high surface tension found in the presence of inadequate
airway narrowing occurs [18, 19] and there is a marked surfactant [50], the airway lumen area would be narrowed
increase in the maximal level of airway resistance. However, or even obstructed.
a decrease in bronchomotor tone will increase airway wall Direct in vivo measurements of airway wall compli-
compliance and lead to dynamic airway narrowing during ance yield conicting results. Measurements from autopsy
maximal expiratory ow [31, 47]. specimens of patients with COPD showed reduced

58
Pulmonary Physiology 5
compliance only in very small (1 mm) airways [51]. typically seen in patients with emphysema [57, 58]. For
Normal lungs show age-related decrease in wall compliance patients with COPD or severe long-standing asthma this
which complicates the interpretation of the losses observed profound alteration in the function and structure of the
in patients with COPD who are normally older [52, 53]. In airway accounts for the sustained and therapeutically resist-
asthma both increases [53, 54] and decreases [21] in wall ant increase in airway resistance or decrease in FEV1. The
stiness have been reported. Decreased wall compliance or dilemma for the clinician is to ascertain what portion of
stiening is likely the result of inammation and/or wall the loss of structure and function is reversible and what
thickening and hence would be related to asthma severity portion is not.
and disease status. Another potential mechanism of airway
narrowing from the increase in wall compliance results from
a decrease in forces tethering the airway open. These forces
are decreased through two mechanisms. First, there are few
alveolar attachments to the outer mucosa of the airway AIRFLOW RESISTANCE
wall and second scar tissue has less tensile strength than
normal tissue [55].
Chronic obstructive pulmonary disease
Tethering forces or the coupling of lung A common feature of the patient with COPD is airow
volume and resistance limitation; this is most often assessed by the fall in FEV1.
The current Global Initiative for Chronic Obstructive Lung
The attachments of the alveolar wall to the external wall of Disease (GOLD) classication system for COPD uses
the intrapulmonary airway are the anatomical link between post-bronchodilator FEV1 as a major factor in classica-
the alveoli of the parenchyma and airway. These attachments tion of disease severity and in practice this variable makes
form the physical linkage system that result in airways wid- up a signicant part of the case denition for COPD [59].
ening and the fall in airways resistance as lung volumes Airow limitation in COPD arises in the small (2 mm
increase. This tethering force is the single most important diameter at FRC) airways which exhibit neutrophilic
factor stabilizing and inuencing airway lumen integrity inammation even in asymptomatic smokers [60, 61].
[1315]. This fact is evidenced by the profound eect lung When patients have mild, asymptomatic disease there are
volume has on airow. As noted above, for a given degree of subtle changes in airow limitation [60] with changes in
smooth muscle activation greater airway narrowing occurs distribution and homogeneity of ventilation. As the severity
at low versus high lung volumes. For example, the simple of COPD increases there is increased involvement of more
act of assuming the supine position, which is not associ- central airways but even when FEV1 has fallen to 5060%
ated with a change in smooth muscle activation, markedly of predicted, more than half of the increased resistance can
increases airway resistance [15, 18]. The eects of lung vol- be attributed to narrowed intrapulmonary (3 mm) airways
ume on airways resistance are very sensitive to even small [42]. Airway dimensions in COPD are reduced, even when
losses (1 cmH2O) in lung elastic recoil pressure [16, 17, 35]. the lungs are inated to a standard ination pressure (typi-
This process is not limited to changes within the parameter cally 30 cmH2O) so one must conclude that the structural
of the airway as denoted by ASM, since changes external remodeling of collagen, mucous gland hyperplasia, general
to the ASM can also uncouple the lung volumeairway wall thickening, and loss of tethering elastic forces contrib-
resistance relationship. utes to the airway narrowing [62].
Changing from the upright to the supine position These alterations in structure and function lead to
leads to airway hyperresponsiveness (AHR) in asthmatics profound ventilatory defects and a loss of collateral ven-
but such changes also occur in normals [18, 56]. The mech- tilation [63, 64]. In turn there is a trapping of gas due to
anism for this phenomenon is most likely the loss of the both long expiratory time constants and check valve-like
tethering forces, as estimated by Pel. These forces pull open processes within the obstructed and emphysematous spaces.
the airway wall as lung volume increases, thus a loss of out- Re-establishment of collateral pathways with intrabronchial,
ward recoil tethering the airway open is termed uncoupling. one-way valves, much like the spiracles of insects, leads to
Airway resistance and lung volume uncoupling occurs rap- deation of these overextended spaces [65] and is currently
idly with sleep onset in the patient with nocturnal asthma being explored as a therapeutic option to the COPD patient
and further uncoupling during the night probably as a result to relieve this trapped gas [66].
of inammatory events, resultant airway wall thickening, In patients with severe COPD expiratory airow lim-
and mechanical uncoupling [21]. In COPD the loss of elas- itation is observed at all lung volumes and often occurs even
tic recoil (Pel) is both greater and more persistent than the when there is a minimal expiratory eort; in these patients
age-dependent loss of recoil that occurs in normal persons, expiratory airow limitation occurs on expiration with each
and when considered in regards to loss of Pel with aging, breath [67]. In more mild cases, the airow limitation is
accounts for the progressive loss of FEV1 over the years. observed only on forced expiration because: (1) ow and
The loss of Pel, together with breaks in alveolar attach- volume during eupnea do not reach their structural limits
ments, results in the increased airway narrowing noted on due to the reserve in the respiratory system and (2) dynamic
forced expiration in patients with obstructive airway dis- hyperination, which increases elastic recoil by increasing
ease [47]. Smooth muscle contraction contributes to severe lung volume, further prevents reaching these limits during
airway narrowing and loss of bronchodilation response eupnea. The pathogenesis of airow limitation in patents

59
Asthma and COPD: Basic Mechanisms and Clinical Management

(A) (B) A
A
100
A

Volume (%TLC)
5

Flow (lps)
A B
3
C
2 D
1

0 10 20 30 0 5 10 15
Flow (lps) Pressure (cmH2O) Pressure (cmH2O)

FIG. 5.4 (A) The role of the loss of lung recoil and airway wall collapse in affecting a fall in maximal expiratory flow (FEV1) can be assessed by constructing
a MFSR curve [73, 74]. (B) The conductance (resistance) of airways downstream of the point (equal pressure point) of airflow limitation is determined as the
slope of V/Pel relationship. This V/Pel relationship or MFSR curve comes from selecting points from the both flowvolume and pressurevolume relationships
at points of isovolume (horizontal dashed lines in A). The dotted line, flowvolume loop is from volume displacement of body plethysmograph whereas
the solid line flowvolume loop is integrated volume from the mouth flow signal. The shaded area in (B) is from normal subjects [75]. MFSR A is the V/Pel
without the effect of gas (airway wall compression) whereas MFSR A includes the effect of compression; the resistance is increased. MFSR B is a patient with
increased resistance (e.g. airway narrowing) of the airways. MFSR C is a patient with emphysema where the sole abnormality is a loss of recoil, airway wall
collapse and lower flow rates. MFSR D is a patient with increased resistance, loss of recoil, and increase pressure (volume) at which the airways close due to
collapse and/or airway dynamic compression shifting the V/Pel relationship to the right.

with COPD or more severe forms of bronchitis and asthma variability and reproducibility of the FEV1 as an outcome
accordingly is quite complex and is a reection of the inter- measure is robust and for this reason the FEV1 is a prin-
play between airway caliber, respiratory muscle function, cipal outcome variable for clinical research. Unfortunately
lung volume, elastic recoil, and airway wall compliance a low FEV1 is not specic for any single cause of airow
[6, 14, 23, 24, 27, 62, 68]. limitation, and other assessments of the loss in airow limi-
The severity of COPD is dened as the post- tation must be made.
bronchodilator FEV1 [59], so it is useful to consider what a Useful insight into the causes of airow limitation can
fall in FEV1 signies. The forced expiratory volume in 1 s be gained by the construction of isovolume pressureow
the FEV1 is a measurement taken from the volumetime curves or maximum ow static recoil (MFSR) relationships
relationship, known as a spirogram, during a forced exhala- which are determined from owvolume and PV relation-
tion from TLC. It is important to remember that the FEV1 ships (Fig. 5.4). To assess artifacts from compression of the
is a volume (liters) not a measure of airow (liters per sec- gas in thorax, lung volume is measured from the volume
ond) but it reects the average airow over the rst second displacement of the chest wall and is obtained by having
of a forced exhalation. A decrease in the FEV1, as a percent- the patient sit in a variable-volume, body plethysmograph.
age of its predicted value, indicates that the patient is unable To measure static recoil an esophageal balloon attached to
to exhale a volume of air in 1 s similar in magnitude to that a pressure transducer is positioned in the lower esophagus
which could be exhaled by a person of the same sex, age, to estimate pleural pressure. The subject then inhales to
and height without lung disease. A considerable number of TLC and expires slowly to construct a deation PV curve
factors inuence the magnitude of the FEV1, but only one (Fig. 5.4A) and then the subject performs a maximal ow
of these factors is airway luminal size. The magnitude of the volume curve. By taking a series of data pairs of ow and
FEV1 is very much inuenced by the size of the inspira- pressure from points of isovolume on the PV and ow
tion prior to beginning the forced expiration (TLC), elas- volume relationship, the MFSR curve can be constructed
tic recoil, airway caliber, airway wall compliance, and size of (Fig. 5.4B).
the lung that is open. In the case of the latter as lung vol- The slope (V/P) of the MFSR curve is resist-
ume is lost by airway closure, lling or destruction, the VC, ance (or its inverse, conductance) of the segment of lung
FVC, and hence FEV1, decreases. It is important to realize upstream of the point and is known as the equal pressure
that FEV1 is a polyvalent index; where polyvalent indices point, that is the point along the airway which Ptm is zero.
are ones in which many factors contribute to the exact value Because there is still elastic recoil of the lung at RV, the
of the index [69]; indeed most measures of lung function MFSR relationship does not intersect with zero pressure.
are polyvalent. Accordingly it is unclear what a low FEV1 Patients with airow limitation will exhibit dierent MFSR
might signify, the cause of the decrease or even the best curves depending upon the cause of the airow limitation.
treatment needed to reverse the loss in FEV1. For patients where airow limitation is solely the result of
Empirically the FEV1 is a very useful measure of loss of static elastic recoil, the slope of the curve is normal;
overall lung function since it relates to morbidity and mor- that is upstream resistance is normal and the loss of airow
tality of COPD, even death due to all causes [70]. The is due solely to the loss of static elastic recoil. However, in
techniques used to measure FEV1 have been well codied a patient with airway narrowing due to inammation, col-
[71, 72]. The general performance and in particular the lagen deposition and/or collapse, the slope is decreased, that

60
Pulmonary Physiology 5
is resistance is elevated. By comparing owvolume curves TABLE 5.2 Criteria recommended for acute bronchodilator responses in
constructed from measuring both lung volumes by integrat- adults [79, 81].
ing the ow at the mouth to lung volume measured by the
chest wall, the role of airway wall compression on the loss of FEV1 (%) FVC (%) Comments
airow can be assessed [76]. The owvolume curve derived ACCP 1525 1525 % of baseline in 2 of 3 tests
from the ow and volume exiting the lung is displaced such
that peak ow occurs at a higher volume but, after this ini- Intermountain 15 15 % of baseline
tial peak, ow is lower at any given volume due to dynamic ATS
airway wall compression. In essence this analysis assesses
the delay in gas exiting the lung; the more dynamic com- ATS 1991 12 12 % of baseline and 200 ml
pression, the more temporal delay. ATS/ERS 2000 12 12 % of baseline and 200 ml
In most patients with COPD, a combination of fac-
tors contributes to airow limitation [7376]. Determining ACCP: American College of Chest Physicians; ATS: American Thoracic Society [79]; ERS:
MSFR relationships can suggest which component might European Respiratory Society [81].
be amenable to treatment; bronchodilation for airway nar-
rowing, pursed lip breathing for airway collapse and lung
volume reduction surgery for improving static elastic recoil. -agonist; however, this enhances the response if the start-
In the case of the latter several studies using this analysis ing baseline of FEV1 or FVC is low. The use of a deni-
have shown that the eect of lung reduction surgery is a tion that includes both an absolute change (e.g. 200 ml)
reduction of RV and the resultant increase in the VC [77] or change expressed as a percent of predicted addresses this
or a more complex response where both a change in volume dilemma.
and a change in resistance occurred [78]. There are several approaches used to deliver bron-
chodilators to patients for assessing reversibility but two to
four pus of albuterol with or without a spacer is the most
common. However, combinations of bronchodilators with
BRONCHIAL RESPONSIVENESS or without an anticholinergic agent or the use of nebulizer
treatments are sometimes used. In this case one adminis-
ters the bronchodilator until side eects are observed or the
Bronchial responsiveness includes either the acute response total dose delivered is used [71, 72, 7981]. A wait period is
to a one-time treatment with a bronchodilator usually a then imposed to allow for the drug to exhibit its physiologi-
2-receptor antagonist or the response to a constrictor cal eects, for example 1520 min in the case of albuterol.
bronchial challenge. Determination of bronchial responsive- Unfortunately techniques to determine bronchodilator
ness better denes and classies patients with airways dis- responsiveness are highly variable between studies and labo-
ease. Bronchial responsiveness assessments are often used as ratories making direct comparison of study results dicult.
major outcome variables in clinical investigations and treat- Bronchodilator responsiveness is commonly meas-
ment trials because of the precision of the measure, its asso- ured as a change in the FEV1 but can also be assessed by
ciation to underlying inammation, the relevance to asthma expiratory owvolume loops, specic airway conductance
triggers, and the changes in bronchial responsiveness as the as determined with a body plethysmograph, or with the
result of treatment. forced oscillation technique. Each technique measures dif-
ferent aspects of lung function and the result obtained may
not be exactly equivalent. Moreover the pattern of the bron-
Bronchodilator responses chodilator response can vary with some patients having a
more central airways response (SGaw), whereas others have
Bronchodilator responsiveness to inhaled bronchodilators a more peripheral lung response as measured with FVC or
is among the factors used to dierentiate between whether the FEV1 [4, 81, 82]. Such ndings are of great interest in
a given patient is to be categorized as COPD or asthma. determining the inferred site of the functional defect such
Professional Society guidelines and position statements as central airways versus peripheral airways and have obvi-
for interpretation of spirometric results [72, 79] discuss ous ramications to drug delivery.
the various consensus criteria used to derive the currently
used bronchodilator criterion that identies a signicant
response as one where a 12% or greater change in the post- Bronchoconstriction responses
bronchodilator FEV1 or FVC from pre-bronchodilator val-
ues and a 200 ml absolute change occurs (Table 5.2). AHR is either a bronchoconstricting response (fall in
Establishing a criterion that indicates a signicant FEV1) to a stimulus that normally does not cause a con-
bronchodilator response has been controversial because of striction or is a heightened bronchoconstriction to the
uncertainty as to just what constitutes a signicant response stimulus. Examples of the former are exercise, cold air, or
[79, 80]. Various authors have suggested criteria that range bradykinin where examples of the latter are histamine and
from 10% to 15% change from baseline, some suggest using methacholine. Airways hyperresponsiveness is often used
a change in percent of predicted or an exact volume change to dene the diagnosis of asthma, however, the presence of
(e.g. 400 ml). Bronchodilator responses are reported as a AHR is not specic since many lung diseases are associated
percent change from the volumes obtained prior to use of a with hyperresponsiveness including COPD [83].

61
Asthma and COPD: Basic Mechanisms and Clinical Management

Over the last 50 years the proposed mechanisms to 60


explain AHR included anything from enhanced choliner-

FEV1, fall (% baseline)


gic tone of the airways to the current focus on pathologic 50 Asthma : Severe
alterations (remodeling) of the airway wall. While airways
smooth muscle usually has a central role in most theories, 40
recent experimental evidence suggests that hypercontrac-
30
tility of the ASM is not always required [84]. Bronchial Asthma : Mild
thermoplasty in which radio frequency energy is applied 20
to airways through the bronchoscope to abate the ASM, Normal
improves asthma symptoms with only modest improve- 10
ments in AHR [85]. This interesting result suggests that the COPD
ASM may not be as essential to AHR as previously thought 0
or may serve other purposes [86]. 0.1 1.0 10 100
AHR is functionally dened as a shift of the dose Methacholine dose
response relationship to an inhaled bronchoconstrictor ago-
nist, for example, methacholine, such that lower amount FIG. 5.5 Dose response curves for the dose of inhaled methacholine
of the agent yields equivalent biological response, that is a (mg/ml) versus FEV1 expressed as a percent decrease from the starting
leftward shift of the doseresponse curve [83]. The inhaled baseline. Data points are individual values up until there is a plateau in
dose of bronchial constricting agent is plotted against the the response or 50% fall in FEV1 has occurred. The dashed line is the PC20
fall in lung function and from this relationship the PC20 that is interpolated. Both mild asthma and COPD patients exhibit leftward
(hyperresponsiveness) shifts of the curve without increase in the maximal
is then measured. The PC20 is the interpolated dose of
response plateau. The patients with severe asthma show marked shift to
inhaled agonist that causes FEV1 to fall exactly 20%. The the left without a plateau. Modified and redrawn from Ref. [91].
PC20, decreases as asthma severity increases [83, 87]. The
relationship between the amount of inhaled bronchocon-
strictor agent and FEV1 often has a plateau in which fur-
Lung volume also inuences AHR based on recent
ther doses of drug illicit smaller and smaller physiological
studies on the eects of deep inspiration (DI). Large TLC
responses. In the case of severe asthmatics often a plateau of
breaths are known to be eective in some but not all asth-
response cannot be demonstrated [8891]. This loss of max-
matics [98]. In some patients DI can even cause bronchoc-
imal response may signify the uncoupling, loss of protec-
onstriction and such a response is associated with the degree
tive mechanisms with resultant severe bronchoconstriction
of airway inammation [99]. A DI can also provide protec-
[90]. In clinical, and most research practice, doseresponse
tion to a subsequent bronchoconstricting response when
relationships are usually not carried out until a plateau is
the DI is performed prior to the inhalation of methacholine
revealed thus the PC20 only assesses the position (sensitiv-
[100]. Loss of this bronchoprotective eect of DI occurs in
ity) of the airways responsiveness relationship (Fig. 5.5).
asthmatic patients with mild disease whereas reversibility
Although there is considerable variability among
of an induced constriction by a DI is only lost as asthma
subjects, AHR is considered present when the PC20, using
becomes more severe [101, 102]. In patents with COPD
methacholine chloride as the bronchoconstrictor agonist, is
the eects of DI are lost and this loss has been shown to be
less than 8 mg/ml [83, 87, 90]. Asthmatics will often dem-
related to the loss of alveolar attachments [103].
onstrate a reduced PC20 even though the FEV1 is normal
at the onset of the test; moreover, the PC20 in most studies
does not correlate with the FEV1 [88, 91]. As methacholine
is well known to stimulate serous secretions from airway
glands and cells, it seems reasonable to suggest the AHR of GAS EXCHANGE
patients with mild to moderate asthma could be viewed as a
measure of increased tendency for airway closure to occur. The respiratory system provides oxygen (O2) and removes
In contrast among patients with COPD there is carbon dioxide (CO2) from the body and failure of this
a correlation of FEV1 to PC20 which suggests more of critical role of gas exchange leads to CO2 retention, hyper-
a structural mechanism for AHR consistent with the capnia, and/or hypoxemia. For ideal gas exchange to occur
observed airway wall thickening [44, 9193]. Moreover the ventilation must be matched with the vascular perfusion
patients with -1-antitrypsin deciency demonstrated an within the individual alveolar gas exchange units. The diu-
elevated response in FEV1 in concert with the loss of elastic sion capacity (DLCO) or transfer factor assesses the passive
recoil [94]. The mechanism of the fall in PC20 in COPD transfer of a test gas, carbon monoxide (CO), from alveolus
also seems unlikely to be the same as asthma since inhaled to the blood. The DLCO test is a frequently used measure-
corticosteroids do not lead to an improvement in AHR for ment in the pulmonary function laboratory and is quite use-
COPD patients [95] whereas inhaled steroids do improve ful in categorizing the dierent types of airway disease.
AHR in asthmatic patients [96]. AHR has important
prognostic value because as AHR increases (PC20 decreases)
there is accelerated decline in FEV1 in patients with COPD Ventilation/perfusion relationship
[97]. Taken together the data provide strong evidence that
the physiological mechanisms that lead to AHR in COPD The concept of ventilation to perfusion matching VA/Q
and asthma are probably quite dierent. is commonly used in understanding how airway disease

62
Pulmonary Physiology 5
pathology aects gas exchange. There are four mechanisms exchange units yet this is not the case [109112]. The
used to explain gas exchange abnormalities and include: (1) apparent explanation would include, preserved uploading
alveolar hypoventilation, (2) impaired O2/CO2 diusion, (3) of oxygen on the hemoglobin due to more than adequate
shunt, and (4) VA/Q mismatch, where the latter mechanism capillary transit time, hypoxic vasoconstriction, redirecting
is by far and away the most common cause of gas exchange blood away from aected areas, and adequate collateral ven-
abnormalities in patients with obstructive lung disease. tilation thus bypassing the closed airway.
During an asthma exacerbation or status asthmati-
cus the presence of a bimodal pattern emerges but even in
Chronic obstructive pulmonary disease this situation little pure shunt is observed. Treatment of the
asthma attack returns this pattern to normal [112] even at
The obstruction of airow to specic regions of the lung time of discharge from the emergency department [114].
parenchyma and widespread airway narrowing coupled with The relative preservation of arterial blood gases up until
the well-described pulmonary vascular abnormalities leads respiratory failure is attributed to the mechanisms covered
to marked VA/Q abnormalities and abnormal arterial blood above and the high ventilatory and cardiac output that
gases. As respiratory failure ensues, alveolar hypoventilation occurs during an attack. Bronchial challenge produces simi-
further contributes to the observed hypercapnia and hypox- lar patterns but it has been noted that the disturbances in
emia [104, 105]. Intrapulmonary shunt is not a major factor gas exchange lag behind the recovery of airow rates [115,
contributing to hypoxemia nor surprisingly is there a signif- 116]. This pattern of recovery does not occur with leuko-
icant contribution of reduced gas diusion probably because triene challenge, presumably because LTD4 causes a more
there is little ventilation of the areas that have emphysema. selective central airway constriction [117]. However, follow-
VA/Q mismatching appears to fully explain the hypoxemia ing exercise-induced bronchospasm airow normalization
of patients with COPD [105, 106]. In the case of very mild occurs after the return of VA/Q to normal, consistent with
disease in the peripheral airways as evidenced by FEV1 of dierent mechanisms of action in contrast to a naturally
80% predicted or greater, patients have an abnormal slope occurring asthma exacerbation [118]. Taken together these
of phase III on the single breath N2 test, a widened A-a O2 ndings suggest that our understanding of gas exchange in
gradient and mild VA/Q mismatch but with a normal PaO2 asthma, unlike COPD, is unclear.
[107]. During an exacerbation of COPD the VA/Q mis- Therapy has a marked eect on gas exchange.
match increases and accounts for about half of the observed Paradoxical hypoxemia has long been noted as a result of
hypoxemia whereas the remainder is low mixed venous O2 acute -agonist administration [119] and has been attrib-
due to increased O2 consumption of the body presumably uted to eects of -agonists on pulmonary blood ow. VA/Q
due to metabolic requirements of the disease [105, 107]. The measurement made after isoproterenol [110] showed tran-
A-a O2 gradient is correlated to emphysema score [108]; sient (5 min) alterations in blood ow to areas low in VA/Q;
hence, the abnormal gas exchange of COPD is explained by however, studies with a more selective -agonist, salbuterol
the pathology of the disease. were without this eect [112, 120].

Asthma Diffusion capacity (transfer factor)


Early studies with the multiple inert gas elimination tech- The diusion capacity, DLCO, is a measure of the disappear-
nique (MIGET) in stable, mild asthmatics showed a bimo- ance of CO, from the alveolus over a 10 s breath hold and is
dal distribution of pulmonary blood ow with about 25% of taken as an index of the total area of potential gas exchange
the blood ow going to units with low (0.1) VA/Q ratios. surface area. Because CO combines at the same site as oxy-
There was no evidence of areas of shunt or areas of high gen on the hemoglobin molecule, blood ow, hematocrit,
VA/Q or increased dead space [109]. However, later studies and cardiac output signicantly inuence the magnitude
showed less of this bimodal distribution and only some of of DLCO. The addition of helium to the test gas mixture
the patients showed this bimodal pattern [110, 111]; whereas inhaled allows for the calculation of the starting concentra-
most patients showed widening of the distribution of blood tion of CO and the determination of the communicating
ow. Patients in this latter study were receiving treatment gas volume by inert gas dilution. The standard single breath
with inhaled glucocorticosteroids which could explain the DLCO yields two useful measurements; the DLCO and a
dierences between studies. The gas exchange abnormali- measurement of TLC (VA) [121].
ties of patients with mild disease were thought to be due to
abnormalities in the periphery and consistent with abnormal
peripheral lung function such as in RV or frequency depend- Asthma & DLCO
ence of compliance. Asthma severity is associated with wid- The DLCO in patients with asthma is either within normal
ening of the VA/Q relationship [112] but most patients still limits or high depending on several factors. In asthmatic
exhibit a near normal PaO2 until they reach the point of patients with preserved lung function, the DLCO is typically
seeking medical assistance (Fig. 5.6) [113]. normal [122]. In moderate to severe asthma the DLCO is
Given that measurements of lung mechanisms show usually elevated and will also increase with bronchodila-
marked increase in peripheral resistance due to airway clo- tor treatment. The high DLCO values [123, 124] have been
sure, one might expect to observe considerable shunting explained by hyperination, increased intrathoracic pressure,
as blood ows by these closed airways and unventilated and a more likely cause, increases in pulmonary capillary

63
Asthma and COPD: Basic Mechanisms and Clinical Management

Normal Episodic asthma


1.5
0.9

1.0
0.6

0.5 0.2

Shunt
0.0 0.0
0.0 0.1 1.0 10 100 0.0 0.01 1.0 100

Chronic severe asthma Acute severe asthma

1.2
Ventilation and blood flow (l/min)

0.6 1.0

0.8
0.4
0.6

0.4
0.2

0.2

0.0 0.0
0.0 0.01 1.0 100 0.0 0.1 1.0 10 100

COPD type A COPD type B


2.0
1.2

0.8
1.0

0.4

0.0
0.0 0.01 0.1 1.0 10 100 0.0 0.01 0.1 1.0 10 100
Ventilation/blood flow ratio

FIG. 5.6 The VA/Q relationship as determined by the multiple inert gas elimination technique (MIGET). Note the different scaling for both axes in the various
examples. The normal distribution of ventilation (open circles) and blood flow (solid circles) is over a narrow range of VA/Q ratios and is unimodal. Patients
with mild or chronic asthma have wider distributions but still exhibit unimodal distributions whereas acute severe asthma is bimodal. In emphysema (COPD,
type A) there is a bimodal distribution in ventilation whereas chronic bronchitis (COPD, type B) exhibits bimodal blood flow. Shunt is not present in any of
the examples. Reproduced from Refs [105, 111] with permission.

blood volume or extravasation of red blood cells into particularly those who are more severe [125]. Increased vac-
the alveolus. Although not frequently commented on or ularization of the lung and airways might also increase the
because current practice is to lyse the lavage sample, the red apparent pulmonary capillary blood volume and account for
blood cell content is high in lavage samples of asthmatics, the elevated DLCO [43].

64
Pulmonary Physiology 5
Chronic obstructive pulmonary disease & DLCO TABLE 5.3 Physiological features of asthma contrasted with COPD.
In contrast to asthma patients with emphysema exhibit
Physiological
a reduction in DLCO [121, 126]. This reduction in DLCO
assessment COPD Asthma
has been shown to be closely related to evidence of patho-
logic emphysema [126] or emphysema as measured by CT Airflow limitation Present Sometimes present
[127, 128]. In asymptomatic smokers there is a detectable
10% decrease in DLCO that reverses with smoking cessa- Loss of elastic recoil Frequently present Sometimes present
tion likely due to reduced pulmonary capillary volume and
Bronchodilator  Usually present
CO back pressure [129, 130]. However, it should be noted
response
that the correlation of the reduction in DLCO to disease
severity in the individual patients is poor, perhaps reecting AHR  
the heterogeneity of the pathology of a given patient. The
DLCO is typically within normal limits for COPD patients Exercise-induced AHR  
with primary chronic bronchitis. One study showed a sig- VA/Q Widened Widened
nicant relationship between the DLCO and 3-year survival
[131], although another study did not nd this to be the DL CO * WNL or
case [132].
Notes: AHR: airways hyperresponsiveness; VA/Q: ventilation to perfusion ration; DL CO:
The measurement of alveolar volume (VA) provides
diffusion capacity of the lung.
additional insight into the physiological derangements * For emphysema, chronic bronchitis would be WNL.
present in the patient with airways obstruction. Because VA
is a single breath dilution of an inspired gas, it is aected
by both the presence of non-communicating lung volume,
TABLE 5.4 Pattern of changes in DL CO and VA in patients with obstructive
for example emphysematous bullae and the long-time con-
lung disease.
stants caused by airways narrowing. In normal subjects, and
when expressed as the volume of gas at body temperature, Clinical condition FEV1 VA DLCO
pressure and fully saturated, the measure of VA will agree
(200 ml) with TLC by body plethysmograph; however, Emphysema
patients with asthma or COPD will exhibit greater than
200 ml dierence between TLC and VA [133]. The degree Bronchitis WNL
of dierence between TLC and VA provides an approxi- Asthma WNL or
mate estimate of the total size of the non-communicating
bullae and alveoli [126, 134] or gas maldistribution. Notes: DL CO: diffusion capacity of carbon monoxide; FEV1: forced expiratory volume in
1 s; WNL: within normal limit.

CONCLUSION coupled with the measurement of spirometry and the


response to a bronchodilator [135137] (Table 5.4).
The clinical presentation of patients with obstructive lung
disease often presents a confusing clinical picture (Table
5.3). Consider, for example, the patient who reports asthma- References
like symptoms to common triggers but who also smokes and
has a greater than 20 pack per year smoking history. Such a 1. Bachert C, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its
patient might be expected to exhibit physiological features impact on asthma. In collaboration with the world health organiza-
of both disorders. This is because the physiological mecha- tion. Executive Summary of the Workshop Report. December 710, 1999,
Geneva, Switzerland. Allergy 57: 841855, 2002.
nisms of asthma and COPD that dier in the details of
2. Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB. The
the inammatory processes, cells, mediators, and pathology proportional Venn diagram of obstructive lung disease: Two approxi-
may be very similar physiologically in terms of hyperina- mations from the United States and the United Kingdom. Chest 124:
tion, loss of static recoil, and expiratory airow limitation. 47481, 2003.
Bronchodilator responsiveness is also not unique to asthma 3. Viegi G, Matteelli G, Angino A, Scognamiglio A, Baldacci S, Soriano JB,
since patients with COPD often demonstrate reversibility Carrozzi L. The proportional Venn diagram of obstructive lung disease
of airow limitation. Bronchial responsiveness is also present in the Italian general population. Chest 126: 1093101, 2004.
in both entities but the response to bronchoconstrictors is 4. Brown RH, Pearse DB, Pyrgos G, Liu MC, Togias A, Permutt S. The
more related to lung function and structure in COPD and structural basis of airways hyperresponsiveness in asthma. J Appl Physiol
the patient with COPD generally does not respond to exer- 101: 3039, 2006.
5. Kraft M, Cairns CB, Ellison MC, Pak J, Irvin C, Wenzel S.
cise by exhibiting bronchospasm. Gas exchange in general
Improvements in distal lung function correlate with asthma symptoms
is similar between both diseases with increased VA/Q mis- after treatment with oral montelukast. Chest 130: 172632, 2006.
match but with little evidence of shunt or global hypoven- 6. Irvin C, Cherniack R. Pathophysiology and physiologic assessment of
tilation. The DLCO represents an important distinguishing the asthmatic patient. Sem Resp Med 8(3): 20115, 1987.
feature between emphysema and other airways diseases and 7. Irvin CG. Lessons from structure-function studies in asthma: Myths
provides a means of discriminating the disease process when and truths about what we teach. J Appl Physiol 101: 79, 2006.

65
Asthma and COPD: Basic Mechanisms and Clinical Management

8. Irvin C. Guide to the evaluation of pulmonary function. In: Hamid Q, 31. De Troyer A, Yernault JC, Rodenstein D. Inuence of beta-2 agonist
Shannon J, Martin J, Hamilton J (eds). Physiologic Basis of Respiratory aerosols on pressurevolume characteristics of the lungs. Am Rev Respir
Disease. Ontario: BC Decker, 2005. Dis 118: 98795, 1978.
9. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, 32. Eidelman DH, Ghezzo H, Kim WD, Hyatt RE, Cosio MG. Pressure
Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CP et al. volume curves in smokers. Comparison with alpha-1-antitrypsin de-
Standardisation of the measurement of lung volumes. Eur Respir J 26: ciency. Am Rev Respir Dis 139: 145258, 1989.
51122, 2005. 33. Wagers SS, Norton RJ, Rinaldi LM, Bates JH, Sobel BE, Irvin CG.
10. Whittaker LA, Irvin CG. Going to extremes of lung volume. J Appl Extravascular brin, plasminogen activator, plasminogen activator
Physiol 102: 83133, 2007. inhibitors, and airway hyperresponsiveness. J Clin Invest 114: 10411,
11. Loring SH, ODonnell CR, Butler JP, Lindholm P, Jacobson F, 2004.
Ferrigno M. Transpulmonary pressures and lung mechanics with glos- 34. Mead J, Takishima T, Leith D. Stress distribution in lungs: A model of
sopharyngeal insuation and exsuation beyond normal lung volumes pulmonary elasticity. J Appl Physiol 28: 596608, 1970.
in competitive breath-hold divers. J Appl Physiol 102: 1846, 2007. 35. Carroll NG, Mutavdzic S, James AL. Increased mast cells and neu-
12. Peress L, Sybrecht G, Macklem PT. The mechanism of increase in total trophils in submucosal mucous glands and mucus plugging in patients
lung capacity during acute asthma. Am J Med 61: 16569, 1976. with asthma. Thorax 57: 67782, 2002.
13. Butler J, Caro CG, Alcala R, Dubois AB. Physiological factors aect- 36. Lundblad LK, Thompson-Figueroa J, Allen GB, Rinaldi L,
ing airway resistance in normal subjects and in patients with obstruc- Norton RJ, Irvin CG, Bates JH. Airway hyperresponsiveness in allergi-
tive respiratory disease. J Clin Invest 39: 58491, 1960. cally inamed mice: The role of airway closure. Am J Respir Crit Care
14. Vincent NJ, Knudson R, Leith DE, Macklem PT, Mead J. Factors Med 175: 76874, 2007.
inuencing pulmonary resistance. J Appl Physiol 29: 23643, 1970. 37. Venegas JG, Winkler T, Musch G, Vidal Melo MF, Layeld D,
15. Briscoe WA, Dubois AB. The relationship between airway resistance, Tgavalekos N, Fischman AJ, Callahan RJ, Bellani G, Harris RS. Self-
airway conductance and lung volume in subjects of dierent age and organized patchiness in asthma as a prelude to catastrophic shifts.
body size. J Clin Invest 37: 127985, 1958. Nature 434: 77782, 2005.
16. Bates JH, Schuessler TF, Dolman C, Eidelman DH. Temporal dynam- 38. Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker ER.
ics of acute isovolume bronchoconstriction in the rat. J Appl Physiol 82: Peripheral lung resistance in normal and asthmatic subjects. Am Rev
5562, 1997. Respir Dis 141: 58488, 1990.
17. Nagase T, Martin JG, Ludwig MS. Comparative study of mechanical 39. Kaminsky DA, Irvin CG, Gurka DA, Feldsien DC, Wagner EM,
interdependence: Eect of lung volume on raw during induced con- Liu MC, Wenzel SE. Peripheral airways responsiveness to cool, dry air
striction. J Appl Physiol 75: 25005, 1993. in normal and asthmatic individuals. Am J Respir Crit Care Med 152:
18. Ding DJ, Martin JG, Macklem PT. Eects of lung volume on maximal 178490, 1995.
methacholine-induced bronchoconstriction in normal humans. J Appl 40. Kraft M, Pak J, Martin RJ, Kaminsky D, Irvin CG. Distal lung dys-
Physiol 62: 132430, 1987. function at night in nocturnal asthma. Am J Respir Crit Care Med 163:
19. Meinero M, Coletta G, Dutto L, Milanese M, Nova G, 155156, 2001.
Sciolla A, Pellegrino R, Brusasco V. Mechanical response to metha- 41. Ohrui T, Yanai M, Sekizawa K, Morikawa M, Sasaki H, Takishima T.
choline and deep inspiration in supine men. J Appl Physiol 102: 26975, Eective site of bronchodilation by beta-adrenergic and anticholinergic
2007. agents in patients with chronic obstructive pulmonary disease: Direct
20. Martin J, Powell E, Shore S, Emrich J, Engel LA. The role of respira- measurement of intrabronchial pressure with a new catheter. Am Rev
tory muscles in the hyperination of bronchial asthma. Am Rev Respir Respir Dis 146: 8891, 1992.
Dis 121: 44147, 1980. 42. Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Site of airway
21. Irvin CG, Pak J, Martin RJ. Airway-parenchyma uncoupling in noc- obstruction in pulmonary disease: Direct measurement of intrabron-
turnal asthma. Am J Respir Crit Care Med 161: 5056, 2000. chial pressure. J Appl Physiol 72: 101623, 1992.
22. Irvin CG. Lung volume: A principle determinant of airway smooth 43. James AL, Wenzel S. Signicance of airway remodeling in airway dis-
muscle function. Eur Respir J 22: 35, 2003. eases. Eur J Respir Dis 30: 142041, 2007.
23. Mead J, Turner JM, Macklem PT, Little JB. Signicance of the rela- 44. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial brosis
tionship between lung recoil and maximum expiratory ow. J Appl in the bronchi of asthmatics. Lancet 1: 52024, 1989.
Physiol 22: 95108, 1967. 45. McParland BE, Macklem PT, Pare PD. Airway wall remodeling:
24. Black LF, Hyatt RE, Stubbs SE. Mechanism of expiratory airow Friend or foe? J Appl Physiol 95: 42634, 2003.
limitation in chronic obstructive pulmonary disease associated with 46. Wiggs BR, Hrousis CA, Drazen JM, Kamm RD. On the mechanism
1-antitrypsin deciency. Am Rev Respir Dis 105: 89199, 1972. of mucosal folding in normal and asthmatic airways. J Appl Physiol 83:
25. Gibson GJ, Pride NB, Davis J, Schroter RC. Exponential descrip- 181421, 1997.
tion of the static pressurevolume curve of normal and diseased lungs. 47. Krowka MJ, Enright PL, Rodarte JR, Hyatt RE. Eect of eort on
Am Rev Respir Dis 120: 799811, 1979. measurement of forced expiratory volume in one second. Am Rev
26. Finucane KE, Colebatch HJ. Elastic behavior of the lung in patients Respir Dis 136: 82933, 1987.
with airway obstruction. J Appl Physiol 26: 33038, 1969. 48. Tandon MK, Campbell AH. Bronchial cartilage in chronic bronchitis.
27. Schlueter DP, Immekus J, Stead WW. Relationship between maximal Thorax 24: 60712, 1969.
inspiratory pressure and total lung capacity (coecient of retraction) in 49. Lambert RK, Codd SL, Alley MR, Pack RJ. Physical determinants of
normal subjects and in patients with emphysema, asthma, and diuse bronchial mucosal folding. J Appl Physiol 77: 120616, 1994.
pulmonary inltration. Am Rev Respir Dis 96: 65665, 1967. 50. Yager D, Butler JP, Bastacky J, Israel E, Smith G, Drazen JM.
28. Gold WM, Kaufman HS, Wadd JA. Elastic recoil of the lungs in Amplication of airway constriction due to liquid lling of airway
chronic asthmatic patients before and after therapy. J Appl Physiol 23: interstices. J Appl Physiol 66: 287384, 1989.
43338, 1967. 51. Wilson AG, Massarella GR, Pride NB. Elastic properties of airways in
29. Woolcock AJ, Read J. The static elastic properties of the lungs in human lungs post mortem. Am Rev Respir Dis 110: 71629, 1974.
asthma. Am Rev Respir Dis 98: 78894, 1968. 52. Maisel JC, Silvers GW, Mitchell RS, Petty TL. Bronchial atrophy and
30. Mansell A, Dubrawsky C, Levison H, Bryan AC, Langer H, dynamic expiratory collapse. Am Rev Respir Dis 98: 98897, 1968.
Collins-Williams C, Orange RP. Lung mechanics in antigen-induced 53. Brackel HJ, Pedersen OF, Mulder PG, Overbeek SE, Kerrebijn KF,
asthma. J Appl Physiol 37: 297301, 1974. Bogaard JM. Central airways behave more stiy during forced expiration

66
Pulmonary Physiology 5
in patients with asthma. Am J Respir Crit Care Med 162: 896904, 74. Pride NB, Permutt S, Riley RL, Bromberger-Barnea B. Determinants
2000. of maximal expiratory ow from the lungs. J Appl Physiol 23: 64662,
54. Wilson JW, Li X, Pain MC. The lack of distensibility of asthmatic air- 1967.
ways. Am Rev Respir Dis 148: 8069, 1993. 75. Leaver DG, Tattereld AE, Pride NB. Contributions of loss of lung
55. Saetta M, Ghezzo H, Kim WD, King M, Angus GE, Wang NS, Cosio recoil and of enhanced airways collapsibility to the airow obstruc-
MG. Loss of alveolar attachments in smokers. A morphometric cor- tion of chronic bronchitis and emphysema. J Clin Invest 52: 211728,
relate of lung function impairment. Am Rev Respir Dis 132: 894900, 1973.
1985. 76. Ingram RH Jr., Schilder DP. Eect of gas compression on pulmonary
56. Skloot G, Permutt S, Togias A. Airway hyperresponsiveness in asthma: pressure, ow, and volume relationship. J Appl Physiol 21: 182126,
A problem of limited smooth muscle relaxation with inspiration. J Clin 1966.
Invest 96: 2393403, 1995. 77. Ingenito EP, Evans RB, Loring SH, Kaczka DW, Rodenhouse JD,
57. Opazo Saez AM, Seow CY, Pare PD. Peripheral airway smooth mus- Body SC, Sugarbaker DJ, Mentzer SJ, DeCamp MM, Reilly JJ Jr..
cle mechanics in obstructive airways disease. Am J Respir Crit Care Med Relation between preoperative inspiratory lung resistance and the out-
161: 91017, 2000. come of lung-volume-reduction surgery for emphysema. N Engl J Med
58. Pare PD, Wiggs BR, James A, Hogg JC, Bosken C. The compara- 338: 118185, 1998.
tive mechanics and morphology of airways in asthma and in chronic 78. Gelb AF, Brenner M, McKenna RJ Jr., Fischel R, Zamel N, Schein MJ.
obstructive pulmonary disease. Am Rev Respir Dis 143: 118993, Serial lung function and elastic recoil 2 years after lung volume reduc-
1991. tion surgery for emphysema. Chest 113: 1497506, 1998.
59. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global 79. ATS. Lung function testing: Selection of reference values and interpre-
strategy for the diagnosis, management, and prevention of chronic tive strategies. Am Rev Respir Dis 144: 120218, 1991.
obstructive pulmonary disease. NHLBI/WHO global initiative for 80. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi
chronic obstructive lung disease (GOLD) workshop summary. Am J R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J
Respir Crit Care Med 163: 125676, 2001. et al. Interpretative strategies for lung function tests. Eur Respir J 26:
60. Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J, 94868, 2005.
Macklem PT. The relations between structural changes in small airways 81. Smith HR, Irvin CG, Cherniack RM. The utility of spirometry in the
and pulmonary-function tests. N Engl J Med 298: 127781, 1978. diagnosis of reversible airways obstruction. Chest 101: 157781, 1992.
61. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the 82. ODonnell DE, Lam M, Webb KA. Spirometric correlates of improve-
peripheral airways of young cigarette smokers. N Engl J Med 291: ment in exercise performance after anticholinergic therapy in chronic
75558, 1974. obstructive pulmonary disease. Am J Respir Crit Care Med 160: 54249,
62. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, 1999.
Cherniack RM, Rogers RM, Sciurba FC, Coxson HO et al. The nature 83. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL,
of small-airway obstruction in chronic obstructive pulmonary disease. Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD et al.
N Engl J Med 350: 264553, 2004. Guidelines for methacholine and exercise challenge testing-1999. This
63. Hogg JC, Macklem PT, Thurlbeck WM. The resistance of collateral ocial statement of the American thoracic society was adopted by
channels in excised human lungs. J Clin Invest 48: 42131, 1969. the ATS board of directors, July 1999. Am J Respir Crit Care Med 161:
64. Terry PB, Traystman RJ, Newball HH, Batra G, Menkes HA. 30929, 2000.
Collateral ventilation in man. N Engl J Med 298: 1015, 1978. 84. Wagers S, Lundblad LK, Ekman M, Irvin CG, Bates JH. The allergic
65. Choong CK, Macklem PT, Pierce JA, Lefrak SS, Woods JC, mouse model of asthma: Normal smooth muscle in an abnormal lung?
Conradi MS, Yablonskiy DA, Hogg JC, Chino K, Cooper JD. Transpleural J Appl Physiol 96: 201927, 2003.
ventilation of explanted human lungs. Thorax 62: 62330, 2007. 85. Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC,
66. Wood DE, McKenna RJ Jr., Yusen RD, Sterman DH, Ost DE, Olivenstein R, Pavord ID, McCormack D, Chaudhuri R et al. Asthma
Springmeyer SC, Gonzalez HX, Mulligan MS, Gildea T, Houck WV control during the year after bronchial thermoplasty. N Engl J Med 356:
et al. A multicenter trial of an intrabronchial valve for treatment of 132737, 2007.
severe emphysema. J Thorac Cardiovasc Surg 133: 6573, 2007. 86. Solway J, Irvin CG. Airway smooth muscle as a target for asthma ther-
67. Eltayara L, Becklake MR, Volta CA, Milic-Emili J. Relationship apy. N Engl J Med 356: 136769, 2007.
between chronic dyspnea and expiratory ow limitation in patients 87. Hargreave FE, Ryan G, Thomson NC, OByrne PM, Latimer K,
with chronic obstructive pulmonary disease. Am J Respir Crit Care Med Juniper EF, Dolovich J. Bronchial responsiveness to histamine or meth-
154: 172634, 1996. acholine in asthma: Measurement and clinical signicance. J Allergy
68. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway Clin Immunol 68: 34755, 1981.
obstruction in chronic obstructive lung disease. N Engl J Med 278: 88. Ryan G, Latimer KM, Dolovich J, Hargreave FE. Bronchial respon-
135560, 1968. siveness to histamine: Relationship to diurnal variation of peak ow
69. Mead J. Problems in interpreting common tests of pulmonary mechan- rate, improvement after bronchodilator, and airway calibre. Thorax 37:
ical function. In: Macklem P, Permutt S (eds). The Lung in Transition 42329, 1982.
Between Death and Disease. New York: Marcel Dekker Inc, 1979. 89. Gibbons WJ, Sharma A, Lougheed D, Macklem PT. Detection of
70. Ferguson GT, Enright PL, Buist AS, Higgins MW. Oce spirometry excessive bronchoconstriction in asthma. Am J Respir Crit Care Med
for lung health assessment in adults: A consensus statement from the 153: 58289, 1996.
national lung health education program. Chest 117: 114661, 2000. 90. Sterk PJ, Bel EH. The shape of the doseresponse curve to inhaled
71. Enright PL, Johnson LR, Connett JE, Voelker H, Buist AS. Spirometry bronchoconstrictor agents in asthma and in chronic obstructive pulmo-
in the lung health study. I: Methods and quality control. Am Rev Respir nary disease. Am Rev Respir Dis 143: 143337, 1991.
Dis 143: 121523, 1991. 91. Woolcock AJ, Anderson SD, Peat JK, Du Toit JI, Zhang YG,
72. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates Smith CM, Salome CM. Characteristics of bronchial hyperresponsive-
A, Crapo R, Enright P, van der Grinten CP, Gustafsson P et al. ness in chronic obstructive pulmonary disease and in asthma. Am Rev
Standardisation of spirometry. Eur Respir J 26: 31938, 2005. Respir Dis 143: 143843, 1991.
73. Fry DL, Hyatt RE. Pulmonary mechanisms: A unied analysis of the 92. Taylor RG, Joyce H, Gross E, Holland F, Pride NB. Bronchial reactiv-
relationship between pressure, volume and gas ow in the lungs of nor- ity to inhaled histamine and annual rate of decline in FEV1 in male
mal and diseased subjects. Am J Physiol 26: 67289, 1960. smokers and ex-smokers. Thorax 40: 916, 1985.

67
Asthma and COPD: Basic Mechanisms and Clinical Management

93. Tashkin DP, Altose MD, Bleecker ER, Connett JE, Kanner RE, 100% oxygen and salbutamol. Am Rev Respir Dis 141: 55862,
Lee WW, Wise R. The lung health study: Airway responsiveness to 1990.
inhaled methacholine in smokers with mild to moderate airow limi- 113. Mountain RD, Sahn SA. Clinical features and outcome in patients
tation. The Lung Health Study Research Group. Am Rev Respir Dis with acute asthma presenting with hypercapnia. Am Rev Respir Dis
145: 30110, 1992. 138: 53539, 1988.
94. Cheung D, Schot R, Zwinderman AH, Zagers H, Dijkman JH, 114. Roca J, Ramis L, Rodriguez-Roisin R, Ballester E, Montserrat JM,
Sterk PJ. Relationship between loss in parenchymal elastic recoil Wagner PD. Serial relationships between ventilationperfusion ine-
pressure and maximal airway narrowing in subjects with alpha1- quality and spirometry in acute severe asthma requiring hospitaliza-
antitrypsin deciency. Am J Respir Crit Care Med 155: 13540, 1997. tion. Am Rev Respir Dis 137: 105561, 1988.
95. Watson A, Lim TK, Joyce H, Pride NB. Failure of inhaled corticos- 115. Rodriguez-Roisin R, Ferrer A, Navajas D, Agusti AG, Wagner PD,
teroids to modify bronchoconstrictor or bronchodilator responsive- Roca J. Ventilationperfusion mismatch after methacholine chal-
ness in middle-aged smokers with mild airow obstruction. Chest lenge in patients with mild bronchial asthma. Am Rev Respir Dis 144:
101: 35055, 1992. 8894, 1991.
96. Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, 116. Echazarreta AL, Gomez FP, Ribas J, Achaval M, Barbera JA, Roca
Sterk PJ. Clinical control and histopathologic outcome of asthma J, Chung KF, Rodriguez-Roisin R. Eects of inhaled furosemide on
when using airway hyperresponsiveness as an additional guide to platelet-activating factor challenge in mild asthma. Eur Respir J 14:
long-term treatment. The AMPUL study group. Am J Respir Crit Care 61621, 1999.
Med 159: 104351, 1999. 117. Echazarreta AL, Dahlen B, Garcia G, Agusti C, Barbera JA, Roca J,
97. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Dahlen SE, Rodriguez-Roisin R. Pulmonary gas exchange and spu-
Wise RA. Methacholine reactivity predicts changes in lung function tum cellular responses to inhaled leukotriene D-4 in asthma. Am J
over time in smokers with early chronic obstructive pulmonary dis- Respir Crit Care Med 164: 2026, 2001.
ease. The Lung Health Study Research Group. Am J Respir Crit Care 118. Young IH, Corte P, Schoeel RE. Pattern and time course of
Med 153: 180211, 1996. ventilationperfusion inequality in exercise-induced asthma. Am Rev
98. Orehek J, Charpin D, Velardocchio JM, Grimaud C. Bronchomotor Respir Dis 125: 30411, 1982.
eect of bronchoconstriction-induced deep inspirations in asthmatics. 119. Knudson RJ, Constantine HP. An eect of isoproterenol on ventila-
Am Rev Respir Dis 121: 297305, 1980. tionperfusion in asthmatic versus normal subjects. J Appl Physiol 22:
99. Lim TK, Pride NB, Ingram RH Jr.. Eects of volume history dur- 4026, 1967.
ing spontaneous and acutely induced air-ow obstruction in asthma. 120. Ballester E, Reyes A, Roca J, Guitart R, Wagner PD, Rodriguez-
Am Rev Respir Dis 135: 59196, 1987. Roisin R. Ventilationperfusion mismatching in acute severe asthma:
100. Scichilone N, Kapsali T, Permutt S, Togias A. Deep inspiration- Eects of salbutamol and 100% oxygen. Thorax 44: 25867, 1989.
induced bronchoprotection is stronger than bronchodilation. Am J 121. Cotton DJ, Graham BL. Single-breath carbon monoxide diusion
Respir Crit Care Med 162: 91016, 2000. capacity or transfer factor. In: Hamid Q, Shannon J, Martin J (eds).
101. Assefa D, Amin N, Dozor AJ. Eect of deep inspiration on airway Physiologic Basis of Respiratory Disease. Hamilton: BC Decker, 2005.
caliber in children with asthma. Pediatr Pulmonol 38: 40612, 2004. 122. Saydain G, Beck KC, Decker PA, Cowl CT, Scanlon PD. Clinical
102. Scichilone N, Marchese R, Soresi S, Interrante A, Togias A, signicance of elevated diusing capacity. Chest 125: 44652, 2004.
Bellia V. Deep inspiration-induced changes in lung volume decrease 123. Keens TG, Mansell A, Krastins IR, Levison H, Bryan AC,
with severity of asthma. Respir Med 101: 95156, 2007. Hyland RH, Zamel N. Evaluation of the single-breath diusing
103. Scichilone N, Bruno A, Marchese R, Vignola AM, Togias A, Bellia V. capacity in asthma and cystic brosis. Chest 76: 4144, 1979.
Association between reduced bronchodilatory eect of deep inspira- 124. Collard P, Njinou B, Nejadnik B, Keyeux A, Frans A. Single breath
tion and loss of alveolar attachments. Respir Res 6: 55, 2005. diusing capacity for carbon monoxide in stable asthma. Chest 105:
104. Begin P, Grassino A. Inspiratory muscle dysfunction and chronic 142629, 1994.
hypercapnia in chronic obstructive pulmonary disease. Am Rev Respir 125. Diaz P, Galleguillos FR, Gonzalez MC, Pantin CF, Kay AB.
Dis 143: 90512, 1991. Bronchoalveolar lavage in asthma: The eect of disodium cromogly-
105. Agusti AG, Barbera JA. Contribution of multiple inert gas elimi- cate (cromolyn) on leukocyte counts, immunoglobulins, and comple-
nation technique to pulmonary medicine. 2. Chronic pulmonary ment. J Allergy Clin Immunol 74: 4148, 1984.
diseases: Chronic obstructive pulmonary disease and idiopathic 126. McLean A, Warren PM, Gillooly M, MacNee W, Lamb D.
pulmonary brosis. Thorax 49: 92432, 1994. Microscopic and macroscopic measurements of emphysema: Relation
106. Hlastala MP, Robertson HT. Inert gas elimination characteristics of to carbon monoxide gas transfer. Thorax 47: 14449, 1992.
the normal and abnormal lung. J Appl Physiol 44: 25866, 1978. 127. Gould GA, MacNee W, McLean A, Warren PM, Redpath A,
107. Barbera JA, Roca J, Ferrer A, Felez MA, Diaz O, Roger N, Best JJ, Lamb D, Flenley DC. CT measurements of lung density
Rodriguez-Roisin R. Mechanisms of worsening gas exchange dur- in life can quantitate distal airspace enlargement An essential den-
ing acute exacerbations of chronic obstructive pulmonary disease. ing feature of human emphysema. Am Rev Respir Dis 137: 38092,
Eur Respir J 10: 128591, 1997. 1988.
108. Barbera JA, Roca J, Ramirez J, Wagner PD, Ussetti P, Rodriguez- 128. Gevenois PA, De Vuyst P, de Maertelaer V, Zanen J, Jacobovitz D,
Roisin R. Gas exchange during exercise in mild chronic obstructive Cosio MG, Yernault JC. Comparison of computed density and micro-
pulmonary disease. Correlation with lung structure. Am Rev Respir scopic morphometry in pulmonary emphysema. Am J Respir Crit Care
Dis 144: 52025, 1991. Med 154: 18792, 1996.
109. Wagner PD, Dantzker DR, Iacovoni VE, Tomlin WC, West JB. 129. Sansores RH, Pare P, Abboud RT. Eect of smoking cessation on
Ventilationperfusion inequality in asymptomatic asthma. Am Rev pulmonary carbon monoxide diusing capacity and capillary blood
Respir Dis 118: 51124, 1978. volume. Am Rev Respir Dis 146: 95964, 1992.
110. Wagner PD, Hedenstierna G, Bylin G. Ventilationperfusion ine- 130. Watson A, Joyce H, Hopper L, Pride NB. Inuence of smoking habits
quality in chronic asthma. Am Rev Respir Dis 136: 60512, 1987. on change in carbon monoxide transfer factor over 10 years in middle
111. Rodriguez-Roisin R, Roca J. Contributions of multiple inert gas aged men. Thorax 48: 11924, 1993.
elimination technique to pulmonary medicine. III: Bronchial asthma. 131. Dubois P, Machiels J, Smeets F, Delwiche JP, Lulling J. CO trans-
Thorax 49: 102733, 1994. fer capacity as a determining factor of survival for severe hypoxae-
112. Ballester E, Roca J, Ramis L, Wagner PD, Rodriguez-Roisin R. mic COPD patients under long-term oxygen therapy. Eur Respir J 3:
Pulmonary gas exchange in severe chronic asthma. Response to 104247, 1990.

68
Pulmonary Physiology 5
132. Anthonisen NR, Wright EC, Hodgkin JE. Prognosis in chronic 136. Klein JS, Gamsu G, Webb WR, Golden JA, Muller NL. High-
obstructive pulmonary disease. Am Rev Respir Dis 133: 1420, 1986. resolution CT diagnosis of emphysema in symptomatic patients
133. Graham BL, Mink JT, Cotton DJ. Eect of breath-hold time on with normal chest radiographs and isolated low diusing capacity.
DLCO(sb) in patients with airway obstruction. J Appl Physiol 58: Radiology 182: 81721, 1992.
131925, 1985. 137. Sciurba FC. Physiologic similarities and dierences between COPD
134. Wade JF 3rd, Mortenson R, Irvin CG. Physiologic evaluation of bul- and asthma. Chest 126: 117S124S, 2004, discussion 159S161S.
lous emphysema. Chest 100: 115154, 1991.
135. Gelb AF, Gold WM, Wright RR, Bruch HR, Nadel JA. Physiologic
diagnosis of subclinical emphysema. Am Rev Respir Dis 107:
5063, 1973.

69
Airway Pathology
6
CHAPTER

NORMAL ANATOMY normal lung because of their much smaller total


James C. Hogg
cross-sectional area [3, 4].
The conducting airways are lined by epi- UBC McDonald Research Laboratories,
The normal human bronchogram (Fig. 6.1) shows thelium and surrounded by an adventitial layer St. Pauls Hospital, University of British
that the length of pathways from the trachea to [5]. The submucosa between the epithelium and Columbia, Vancouver, BC, Canada
the terminal airways diers depending on the outer edge of the muscle layer is often referred
pathway followed and it can take as few as 8 or to as the lamina propria, but this term is tech-
as many as 24 divisions of airway branching to nically incorrect because many airways are not
reach the gas-exchanging surface [1]. The small completely surrounded by muscle [6]. Bronchi are
bronchi and bronchioles 2 mm in diameter are dened by the presence of a layer of brocartilage
spread out from the fourth to the fourteenth external to the smooth muscle and tubuloalveo-
generation of airway branching [2]. The total air- lar glands, which communicate with the airway
way cross-sectional area expands rapidly beyond lumen via ducts [7]. Bronchioles lack both carti-
the 2 mm airways to provide for rapid diusion lage and glands and become respiratory bronchi-
of gas between the distal conducting airways and oles when alveoli open directly into their lumen
the gas-exchanging surface. The central conduct- [7]. The lining of the trachea and major bronchi
ing airways larger than 2 mm internal diameter consists of pseudostratied, ciliated columnar epi-
are the major site of resistance to airow in the thelium which gradually becomes more cuboidal

FIG. 6.1 Postmortem bronchogram from


an otherwise normal 19-year-old man who
died suddenly for reasons unrelated to the
lung. Note the difference in airway length
depending upon the pathway that is followed.

71
Asthma and COPD: Basic Mechanisms and Clinical Management

FIG. 6.2 Photomicrograph of a bronchiole from a patient who died of asthma. This shows the location of submucosal capillaries (white arrow), connecting
vessels passing between muscle bundles (dark arrow) to larger postcapillary venules located outside the muscle layer. On the right, the same features are
shown at a higher magnification.

with fewer ciliated cells as the alveolar surface is approached the third intercostal artery, from the right internal mammary
[68]. Light microscopy reveals that the basal aspect of air- artery, or from the right subclavian artery [8, 15]. Millers
way epithelial cells is attached to a thin basement membrane classic anatomical account [8] showed that two to three
(8090 nm width) that contains primarily type IV collagen arterial branches accompany each of the larger bronchi and
and elastin [9]. Transmission electron microscopy shows that that anastomoses between these branches form an arterial
a true basement membrane or basal lamina can be readily dis- plexus in the outer wall of the airway. Small branches of this
tinguished from the connective tissue observed with the light plexus penetrate the smooth muscle layer to form a capillary
microscope [6, 7]. Quantitative studies [1012] have shown network below the epithelium. Short connecting branches
that the trachea and mainstem bronchi of normal subjects extend from this plexus through the muscle layer to form a
consist of by volume: second plexus of venules along the outer surface of the airway
30% cartilage; smooth muscle (Fig. 6.2). In some species, this outer plexus
contains large venous sinuses that can extend into the sub-
15% mucous glands; mucosal layer of the major bronchi, where there is no smooth
5% smooth muscle; and muscle between the cartilage and epithelium [16].
The venous blood from the rst two or three subdivi-
50% connective tissue matrix containing the bronchial sions of the bronchial tree drains into the azygous and hemi-
arterial, venous, and lymphatic vessels. azygous venous systems that empty into the vena cava. The
With progression toward the periphery of the bronchial remainder of the bronchial venous ow drains directly into
tree, the amount of cartilage and glands decrease, and the the pulmonary circulation, although there is debate as to how
percentage of smooth muscle increases to account for approx- much enters at the precapillary, capillary, and postcapillary
imately 20% of the total wall thickness in the bronchioles. levels [8, 15]. Airway disease increases the anastomotic ow
The degree to which the smooth muscle surrounds between the pulmonary and the bronchial vascular systems;
the airway lumen varies according to site. In the trachea and in diseases such as bronchiectasis, injection of the bron-
and mainstem bronchi, the airway smooth muscle is located chial arteries can result in rapid lling of the entire pulmo-
within the posterior membranous sheath, whereas, in the nary vascular tree right back to the pulmonic valve [15].
bronchioles, it surrounds the entire lumen of the airway [7, The bronchial circulation accounts for about 1% of car-
8, 13]. Consequently, the same degree of muscle shortening diac output and an average cardiac output of 5 l/min deliv-
has a smaller eect on the caliber of the trachea and cen- ers approximately 72 l of blood to the conducting airways
tral airways than on the distal bronchi and bronchioles [14]. over 24 h. Each liter of blood contains between 4 and
The adventitial layer consists of loose bundles of collagen 11 109 white blood cells, made up of approximately 60%
admixed with blood vessels, lymphatics, and nerves. In the neutrophils, 30% lymphocytes, 5% monocytes, 3% eosi-
peripheral conducting airways, this layer interacts with the nophils, and 2% basophils. The neutrophils do not divide after
surrounding lung parenchyma through alveolar attachments they leave the marrow have a relatively short half life within
that are distributed along the circumference of the adventi- the circulation and remain within the vascular space unless
tia. These alveolar attachments have the ability to limit the an inammatory response is present. Although much less is
amount of airway narrowing produced by smooth muscle known about eosinophils and basophil kinetics they are pre-
contraction, particularly at higher lung volumes [14]. dominately a tissue cell, indicating that their transit times
The systemic arterial supply to the bronchial tree origi- through the tissue compartment is much longer than that for
nates from the ventral side of the upper thoracic aorta in the migrating neutrophils. Monocytes on the other hand leave the
left hemithorax, while on the right the origin of the bronchial vascular space even in the absence of an inammatory stimu-
vessels is more variable. They may originate from the rst to lus and divide in the tissue to form the alveolar macrophages

72
Airway Pathology 6

FIG. 6.3 (A) Shows a small bronchiole with a collection of lymphocytes containing a germinal center. (B) Shows another airway containing a lymphoid
follicle where the germinal center stains strongly for B-cells. (C) Shows the same airway as in B where the CD4 cells appear at the edge of the follicle. (D)
Shows yet another area where the wall is thickened and fibrosed and the arrow pints to the smooth muscle in the airway wall. Adapted from Ref. [17] with
permission.

that are removed via the airways with very little if any re-entry of the follicle and the CD4 and CD8 T-cells are located
into the tissue. On the other hand lymphocytes leave the cir- around the edges of the germinal center. Thus dendritic cells
culation regularly with the assistance of specialized high migrating from the epithelium and subepithelium circulate
endothelial cells and re-entering the circulating blood with through the T- and B-cell rich regions of the follicle and can
the lymph as it drains into the venous system. present antigen to uncommitted T and B lymphocytes moving
A study of lung tissue obtained from patients at all through these regions in the lymph (Fig. 6.3). Moreover the
ve Global Initiative for Chronic Obstructive Lung Disease recirculation of lymphocytes though the follicle and back into
(GOLD) categories of chronic obstructive pulmonary dis- the circulation enhances the opportunity for T Helper cells
ease (COPD) severity has shown an association between the and B-cells that have recognized the same antigen to interact
decrease in FEV1 with both the extent of the accumulation of with each other and initiate an adaptive immune response. The
these cells (i.e. the percentage of airways containing cells) and appearance of lymphoid follicles with germinal centers in the
severity of this accumulation (i.e. the total accumulated vol- tissue provides histological evidence that an adaptive immune
ume of cells) within small airway tissue [17]. The accumulat- response has been mounted within the peripheral lung. Some
ing lymphocytes form follicles with germinal centers in both investigators have begun to study this response in detail [18].
the small conducting airways [17] and the parenchyma [18] of
the peripheral lung in both COPD [17, 18] and asthma [19].
These accumulations of lymphocytes (Fig. 6.3) are part of the
bronchial associated lymphoid system or bronchial-alveolar THE PATHOLOGY OF ASTHMA
lymphoid tissue (BALT) and dier from the regional lymph
nodes in that they have no capsule and no aerent lymphat-
ics. They are similar in structure to the tonsils and adenoids, Postmortem studies
the Peyers patches in the small bowel, and the appendix of
the cecum which are also part of the mucosal immune system. At postmortem, the lungs of patients who have died in sta-
They are organized in the same way as other lymph follicles tus asthmaticus remain markedly hyperinated after the
(Fig. 6.3) in that the B-cells are found in the germinal center thorax is opened. This hyperination is due to air trapping

73
Asthma and COPD: Basic Mechanisms and Clinical Management

caused by widespread plugging of the segmental, subseg- these cells can be divided according to the cytokine mes-
mental, and the smaller conducting airways by mucus and senger RNA (mRNA) and proteins that they produce [35].
cellular debris [20]. Although this luminal content may These experiments established that one type of T-cell clone
extend to the respiratory bronchioles, it usually stops short (Th-1) produced IL-2 and interferon- but no IL-4 or
of these structures and does not ll the alveolar airspaces. IL-5; whereas the second (Th-2) produced IL-4 and IL-5,
Examination of the cut surface of the lung reveals the but no IL-2 or interferon-. Both clones produced IL-3
plugged airways, but in contrast to parenchymal destruc- and GMCSF, and interactions between Th-1 and Th-2
tion seen in hyperinated emphysematous lungs the subtypes allowed one type of clone to inhibit the other. For
parenchyma of the asthmatic lung remains intact. example, IL-4 is a mast cell growth factor that also stimu-
Huber and Koesslers [21] classic 1922 paper on the lates IgE production, and IL-5 promotes the dierentiation
pathology of asthma reviewed 15 published cases and pro- and survival of eosinophils. Robinson and associates [36]
vided new data on 6 more. They noted that the pathology put forward the hypothesis that asthma was the result of a
consisted of common features that allowed asthma to be Th-2 response based on bronchoalveolar lavage and bron-
distinguished from other conditions. They emphasized the chial biopsy ndings. And subsequent studies of surgically
presence of intraluminal mucus secretion, airway epithelial resected lung specimens from asthmatic patients estab-
desquamation, and repair (e.g. goblet cell metaplasia), and lished that a similar inammatory process was present in
airway inammatory inltrates consisting of an admixture the smaller airways [37].
of mononuclear cells and eosinophils and the presence of a It has now become clear that the structural features of
thickened, hyalinized subepithelial basement membrane. the airways from asthmatic patients result from an inam-
Later studies based on electron microscopy and immuno- matory process involving tissue with a mucus-secreting
histochemistry showed that this feature of the basement surface. This response appears to be driven by a subset of
membrane was due to deposition of collagen brils and CD4 T lymphocytes producing cytokines that result in
extracellular matrix below the true basement membrane, an excess of eosinophils and an overproduction of IgE. The
rather than thickening of the basal lamina. Huber and end result is abnormal airway function, characterized by
Koesslers report noted that the tenacious plugs that ll excessive airway narrowing in response to external stimuli,
the airway lumen consist of an exudate of plasma contain- reversible airways obstruction, and gas trapping. Although
ing inammatory cells, particularly eosinophils, mixed with the majority of the symptoms produced by the process can
epithelial cells that had sloughed from the airway surface. be rapidly reversed with appropriate treatment, the process
Using an eyepiece micrometer to measure the external air- can be life threatening and result in sudden death.
way diameters, they concluded that the walls of bronchi and
bronchioli of more than 2 mm outside diameter were thick-
ened compared with non-asthmatic persons, and that this The relationship between airway structure
dierence was due to an increased thickness of all of the and function
components of the airway wall.
Over the next several decades, other reports con- The concept that the same degree of smooth muscle short-
rmed and extended these ndings [2229]. Comparing ening will cause greater reduction in airway caliber when
Floreys [30] basic studies of the inammatory process with the wall is thickened by disease has been suggested by sev-
these pathological ndings show that the structural changes eral authors [38, 39]. Moreno and associates [39] calculated
associated with asthma are consistent with an inamma- that the thickening of the airway wall observed in asthma
tory process involving a mucus-secreting surface. However, would have only a minor eect on the caliber of the lumen
this knowledge had relatively little impact on the allergists, of a fully dilated airway. However, when the smooth mus-
pulmonary physicians, and physiologists until the 1970s cle in the airway shortens, the increased tissue between
[31], because they were preoccupied with the concept that the muscle and lumen causes an excess reduction in airway
asthma was due to IgE sensitized mast cells releasing medi- caliber. Subsequent studies by James et al. [40] showed that
ators that caused excessive contraction of airway smooth the increase in wall thickness observed in the small airways
muscle following specic antigen challenge. of asthmatics was sucient to close the lumen of these
airways, even when smooth muscle shortening remained
within the accepted normal range. This suggests that normal
Bronchoscopic studies smooth muscle shortening may act in series with an abnor-
mally thickened airway wall to narrow the airway lumen
The nature of the airway pathology in persons with asthma and it follows that the reduction in airway caliber pro-
was further revealed by studies of tissue obtained through the duced by this mechanism would be rapidly reversed when
rigid and exible bronchoscope. These techniques allowed the smooth muscle relaxed. This showed that an important
investigators to obtain cells from living asthmatic patients by feature of the pathology of asthma was the change in the
both bronchoalveolar lavage and bronchial biopsies [3134]. structure of the airway wall produced by the remodeling
This brought physiologists and clinicians into closer agree- of the tissue that occurs in relation to the inammatory
ment with the pathologists view that the inammatory process. The important point is that these structural changes
process was important to the pathogenesis of both bronchial could result in excess airway narrowing with normal smooth
hyperresponsiveness and reversible airow obstruction. muscle contraction and that excessive smooth muscle short-
A very important conceptual development based on ening will enhance the eect of these structural changes on
the discovery that murine CD4 T-cell clones showed that the airway lumen.

74
Airway Pathology 6
(A) 20 Wiggs et al. [41, 42] extended this concept using a
18
computer model to test the eect of these structural changes
Asthma on airway function. Their analysis (Fig. 6.4) showed that
Total
16 maximum stimulation of the smooth muscle caused air-
14 way resistance to increase and reach a plateau in the normal
lung. This nding was consistent with previous observations
Resistance

12
10
by Woolcock et al. [43], who reported that the changes in
Control
the maximum volume of air that can be expired from the
8
lung in 1 s (FEV1) reached a plateau in normal subjects
6 when maximally stimulated by inhaled bronchoconstrictors.
4 However, when the data on airway structure were changed
2 from normal values to those found in asthmatic lungs, a
similar degree of airway smooth shortening resulted in a
0
sustained rapid increase in airway resistance without a pla-
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
teau. When the eect of disease on the central and periph-
(B) 20 eral airway function was examined separately, they found
18 Asthma that the increase in airway resistance was primarily due
Central to the eect of disease on the peripheral airways, where
16
smooth muscle shortening produced widespread airway clo-
14
sure. The concept that the peripheral airways are the major
Resistance

12 site of obstruction in asthma has now been conrmed by


10 Control direct measurements in living asthmatic patients reported
8 by Yanai et al. [44].
The changes that are produced in the airway tis-
6
sue also reduce the function of the conducting airways.
4 Lambert [45] was the rst to systematically study the nor-
2 mal folding pattern of the bronchial mucosa, and showed
0 that in asthma the multiple mucosal folds that occur when
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 normal airways narrow were replaced with fewer and larger
(C) 20 folds that reduced airway caliber. Both Lambert and Wiggs
18
et al. [46] suggested that the mucosal folding pattern was
Asthma controlled by the stiness of the subepithelial layer rela-
Peripheral
16 tive to that of the surrounding airway tissue. This analysis
14 suggested that changes in the subepithelial connective tis-
sue might play a key role in determining the pattern of
Resistance

12
10
mucosal folding. Lambert and Wiggs et al. argued that the
Control
formation of a large number of folds in the normal airway
8 placed a load on the airway smooth muscle that tended
6 to prevent airway closure at low lung volumes. It followed
4 that a change in the mucosal folding pattern in asthma may
2 be one way in which this disease causes peripheral airway
dysfunction.
0
The caliber of the airway lumen is also inuenced by
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
airway surface tension that is normally low in the small air-
Log (dose)
ways because they are lined with surfactant [47]. Exudation
FIG. 6.4 Data from Wiggs et al. (Refs. [38, 39]) showing results from a
of plasma and the secretion of mucus on to the small airway
computer model of the airways. The structural data from normal lungs lumen surface should increase surface tension and cause the
were used to obtain the control measurements. These show that airway airways to narrow. The analysis of induced sputum has con-
resistance increases from about 1 cmH2O per liter per second to reach a rmed that plasma proteins, mucus, and inammatory cells
plateau of 12 cmH2O per liter per second, with maximum contraction of are present in the airway lumen even in mild asthma, sug-
the airways smooth muscle. (A) When the structural features of asthmatic gesting that some of the abnormalities in airway function of
airways were used in the same computer model, the airway resistance asthmatics might result from the presence of this material in
continued to increase and did not reach a plateau at any physiologically the lumen. Kuyper and colleagues [48] recently re-assessed
meaningful value. (B) Data obtained from the model when the structural the importance of the occlusion of the airway lumen by
changes caused by asthma were limited to the central airway (i.e. those
inammatory exudates in deaths attributed to asthma. By
2 mm diameter). Note that asthmatic changes in the central airways
increased total resistance and resulted in a plateau slightly greater than the
examining the airway wall and luminal content of 275 air-
control lungs. (C) However, when the asthmatic changes were placed in ways from 93 patients with fatal asthma aged 1049 years.
the peripheral airway, the resistance increased without reaching a plateau. Compared with control airways obtained from persons that
These data suggest that asthmatic changes in the peripheral airways have died of causes unrelated to the lungs, the asthmatic airways
a much greater effect on overall airway function than changes that occur in showed much more extensive lumenal occlusion, by mucus
the central airways. Reproduced from Ref. [38] with permission. and cells. They concluded that widespread airway occlusion

75
Asthma and COPD: Basic Mechanisms and Clinical Management

was the major cause of death from asthma and death due to
closure of empty airways by excessive bronchoconstriction
must be a rare event. Moreover the extensive nature of the
airway occlusion observed at autopsy in these cases suggests
that bronchoconstriction superimposed on airways that
have become partially occluded is the most probable cause
of sudden death.

THE PATHOLOGY OF COPD

The inammatory process contributes to the pathogenesis of


chronic cough and sputum production [49], peripheral air-
ways obstruction [3, 17, 50], and emphysematous destruc-
tion of the lung surface [51] that dene COPD. As tobacco
smoking produces lung inammation in everyone, and only
1520% of heavy smokers develop COPD, clinical disease
from cigarette smoke-induced airway inammation must
develop in this minority of people because it amplied by
either genetic or environmental risk factors [52].

Chronic bronchitis
Cough and sputum production are the features of airways FIG. 6.5 Low-power photomicrograph of a normal bronchus showing
disease that dene chronic bronchitis [53] and these symp- the opening of a bronchial gland duct into the lumen and its connection
toms can be present either with or without airways obstruc- with the submucosal gland. The bronchial muscle and cartilage are clearly
tion [49]. Figure 6.5 shows the histology of a normal labeled. The inflammatory process associated with chronic bronchitis
bronchus at low power where with the connection between involves the mucosa, gland ducts, and glands of the bronchi that are
between 2 and 4 mm internal diameter. Original photograph taken by the
the epithelial lining of the bronchial lumen to the mucus
late Dr. William Thurlbeck.
duct and gland is clearly seen. Reid [54] used the relative
size of the mucus glands to the airway wall as a yardstick for
measuring chronic bronchitis and downplayed the inuence
of inammation in driving mucus production. However, a The site of airways obstruction
reevaluation of this problem some years later showed that
chronic bronchitis was associated with inammation of The site of airways obstruction in COPD is in the smaller
the airway mucosal surface, the submucosal glands, and conducting airways that include bronchi and bronchioles of
gland ducts, particularly in the smaller bronchi between less than 2 mm diameter [3]. Direct measurements of air-
2 and 4 mm in diameter [49]. The nature of the inam- ways resistance in dogs [4] and in similar measurements
matory process present in these airways is now quite well in postmortem human lungs [3] established, in the normal
established with several studies reporting that CD8 lym- lung, that the small peripheral airways oer very little resist-
phocytes are present in excess numbers in smokers with ance to air ow. Although van Brabant et al. [63] subse-
chronic bronchitis [55, 56]. quently argued that these peripheral airways account for a
Sputum production represents the clearance of a larger proportion of the total airways resistance in the nor-
mucoid inammatory exudate from the lumen of the bronchi. mal lung, there is general agreement that the peripheral air-
This exudate contains plasma proteins, inammatory cells, ways are the major site of obstruction in COPD [3, 44, 63].
and small amounts of mucus added from goblet cells on the The causes of the reduced forced expiratory ow that
surface epithelium and the epithelial glands. Although the dene COPD include destruction of alveolar support of
size of the bronchial mucous glands tends to increase [49] the peripheral airways [64], the loss of elastic recoil in the
in chronic bronchitis, Thurlbeck and Angus [57] showed parenchyma supporting the airways [65], a decrease in the
that the Reid index was normally distributed with no clear elastic force available to drive ow out of the lung [66], and
separation between patients with chronic bronchitis and structural narrowing of the airway lumen by a remodeling
controls. Chronic bronchitis also results in an increase in process [3, 17, 67]. Comparison of the histological appear-
airway smooth muscle, a generalized increase in the con- ance of peripheral airways at dierent degrees of severity of
nective tissue in the airway wall, degenerative changes COPD shows a progressive increase in the magnitude of the
in the airway cartilage, and a shift in epithelial cell type inammatory process with thickening of the airway walls
that increases the number of goblet and squamous cells accompanied by occlusion of the airway lumen by inamma-
[5862]. tory mucous exudates [17]. However, multivariate analysis of

76
Airway Pathology 6

FIG. 6.6 (A) Shows a small bronchiole from a patient with severe (GOLD-4) COPD the lumen is nearly fully occluded and the mucosa is folded because it
was fixed in a collapsed state. (B) Shows a redrawing of the same airway where the lumen occlusion is less severe because the airway has been fully inflated
by removing the folds from the mucosa using a computer (C) Compares the frequency distribution of the ratio of luminal content area to the total area of
the lumen for 562 airways from 42 patients with GOLD-4 COPD before and after the expansion of the lumen shown in A and B. As we do not breathe at
either full expansion of the lung or at minimal volume many airways must have been partially or fully occluded in the normal breathing range. (D) Shows the
relationship between the severity of the occlusion of the airway lumen with the level of FEV1. Adapted from Ref. [17] with permission.

these data indicated that thickening of the airway walls and Emphysema
the occlusion of the lumen by inammatory exudates con-
taining mucus explained more of the variance in the decline Emphysema has been dened as abnormal permanent
in FEV1 than the inltration of the airway tissue by any of enlargement of airspaces distal to terminal bronchioles,
the inammatory cell types examined [17]. Interestingly the accompanied by destruction of their walls without obvi-
severity of the occlusion of the airways lumen by inamma- ous brosis [79]. This denition emphasizes the destruction
tory exudates containing mucus (Fig. 6.6) has also associated of the alveolar surface with a minimal reparative response in
with premature death in persons with severe (GOLD-3) and the lung matrix and the ability of this destructive process to
very severe (GOLD-4) disease [68]. reduce the gas-exchanging surface of the lung. The centrilob-
The lung inammatory changes that are associated ular form of emphysema (Fig. 6.7) resulting from dilatation
with cigarette smoking have been documented in autopsy and destruction of the respiratory bronchioles in the center of
studies [6973], resected lung specimens [4951, 74] lung secondary lobule of Miller has been most closely associated
biopsies [75], and indirectly by examining bronchoalveolar with smoking [80, 82]. The panacinar form of emphysema, on
lavage uid [7678]. Collectively these data support the the other hand, results from a uniform destruction of all of
concept that cigarette smoke-induced lung inammation the acini in the entire secondary lobule and is characteristic
is present in all smokers, including those with normal lung of the lesions found in the lungs in 1-antitrypsin deciency
function and that it persists long after people have stopped [83]. The terms distal acinar, mantle, or periseptal emphy-
smoking [17]. The reasons for both the amplication of the sema are used to describe lesions that occur in the periphery
smoking-related inammatory process in individual that of the lobule and along the lobular septae particularly in the
develop COPD, the persistence of this response after the subpleural region. These lesions have been associated with
smoking has stopped and the precise relationship between spontaneous pneumothorax in young adults and bullous lung
the inammatory response and the remodeling process disease in older individuals [84]. In far-advanced parenchy-
needs further clarication. mal destruction such as that frequently observed in end-stage

77
Asthma and COPD: Basic Mechanisms and Clinical Management

(A) (B)

(C) (D)

CLE
TB

FIG. 6.7 (A) Normal lung photographed from the pleural surface after a postmortem bronchogram. The connective tissue outlining the secondary lobule
is clearly seen (solid arrow) and a terminal bronchiole (TB) indicated by a clear arrow supplies a single acinus. (B) Photomicrograph of an acinus showing a
terminal bronchiole (TB), respiratory bronchiole (RB), and alveolar ducts (AD). Their structure is represented by the fine spray of contrast at the end of the TB
shown in the bronchogram in (A). (C) Diagram of the lesion in centrilobular emphysema, showing the dilation and destruction of the respiratory bronchioles.
(D) Postmortem bronchogram showing a centrilobular emphysematous lesion (CLE) outlined by bronchographic material. Parts (C) and (D) reproduced from
Refs [80, 81], with permission.

COPD, these descriptive terms are less helpful because centri- arrhythmia, pulmonary embolism, pneumothorax, postop-
lobular disease eventually destroys the entire lung lobule and erative complications, and lung cancer [86], with no cause
destroyed lobules can coalesce to form much larger lesions. being established in 303 (25%) of these 1205 admissions.
The destruction of the lung by centrilobular emphy- Early studies by Stuart-Harris and associates [87, 88] showed
sema results in a loss of elastic recoil with subsequent that COPD patients with acute upper respiratory infec-
hyperination and a change in the pressurevolume rela- tions are more likely to have signs of infection in the lower
tionship of the emphysematous lung tissue compared to airways than normal controls. Probably because acute viral
the surrounding normal lung such that at any volume recoil upper respiratory tract infections increase the risk of aspira-
pressure is less [81]. This decrease in lung elastic recoil tion of mucoid exudate containing large numbers of bacte-
diminishes expiratory ow by reducing the pressure avail- ria from the upper airways, but also because viral infection
able to drive air out of the lung [66], and interferes with gas reduces both the mucociliary clearance and bacterial kill-
exchange by reducing lung surface area [85]. ing in the lower airways [8991]. Streptococcus pneumonia,
Staphylococcus aureus, and Hemophilus inuenzae are the most
common bacteria infecting the lower airways during an acute
Acute exacerbations of COPD viral infection [90, 91], and these infections account for the
positive eect of antibiotics in some exacerbations of COPD
In a hospital-based study of 1205 admissions to ve hospi- [92]. Two important early studies established an association
tals for acute exacerbations of COPD, infections accounted between acute illness and serologic laboratory evidence of
for 520 (43%), heart failure for 260 (22%), and 122 (10%) viral infection in patients with COPD [93, 94]. The devel-
cases were attributed to a variety of etiologies that included opment of polymerized chain reaction (PCR)-based viral

78
Airway Pathology 6
diagnostic techniques have improved the sensitivity of the References
diagnosis of viral infection and the use of real time PCR to
measure viral copy numbers will likely improve its specicity. 1. Horseld K, Cumming G. Morphology of the bronchial tree in man.
Early reports of studies based on these techniques indicate J Appl Physiol 24: 37383, 1968.
the importance of rhinoviral infection in causing acute exac- 2. Weibel ER. Morphometry of the Human Lung. New York: Academic
erbations in an outpatient setting with inuenza A and the Press, 1963.
corona virus OC-43 being more prominent causes of exacer- 3. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airways
bations that require admission to hospital [9597]. obstruction in chronic obstructive lung disease. N Engl J Med 48:
The pathological features of the lung during acute 42131, 1968.
4. Macklem PT, Mead J. Resistance of central and peripheral airways
exacerbations of COPD are incompletely dened. Primarily
measured by a retrograde catheter. J Appl Physiol 22: 395401, 1967.
because postmortem studies of patients that die during 5. Bai A, Eidelman DH, Hogg JC et al. Proposed nomenclature for
exacerbations are complicated by terminal events and biopsy quantifying subdivisions of the bronchial wall. J Appl Physiol 77:
studies of patients with severe (GOLD-3 and very severe 101114, 1994.
GOLD-4 disease during an exacerbation cannot be car- 6. Neutra M, Podykula H, Weiss L Histology, Cell and Tissue Biology, 5th
ried out without excess risk to the patient. One exception edn, pp. 658706. Amsterdam: Elsevier Biomedical, 1983.
is an important study by Saetta et al. [98] in less severely 7. Weiss L (ed.), Histology, Cell and Tissue Biology, 5th edn, pp. 788868.
ill patients with GOLD class 2 disease and a mean FEV1 Amsterdam: Elsevier Biomedical, 1983.
of 62  7% predicted implicated the eosinophil as a cell of 8. Miller WS. The blood vessels in the lung. The Lung, 3rd edn, pp. 7384.
interest. Clearly more studies especially those that can make Springeld, IL: Charles Thomas, 1943.
9. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial brosis
use of non-invasive or less invasive techniques than biopsy
in the bronchi of asthmatics. Lancet i: 52024, 1989.
are needed to help clarify this important area of COPD. 10. Dunnill MS. The pathology of asthma with special reference to changes
in the bronchial mucosa. J Clin Pathol 13: 2733, 1960.
11. Dunnill MS. Quantitative methods in the study of pulmonary pathol-
ogy. Thorax 17: 32028, 1962.
12. Takizawa T, Thurlbeck WM. Muscle and mucous gland size in the
SUMMARY major bronchi of patients with chronic bronchitis, asthma and asth-
matic bronchitis. Am Rev Respir Dis 104: 33136, 1971.
13. Plopper CG. Ten Have-Opbroek AAW Anatomical and histologi-
Asthma cal classication of the bronchioles. In: Epler GR (ed.), Diseases of the
Bronchioles, pp. 1525. New York: Raven Press, 1994.
The pathology of asthma is dominated by widespread plug- 14. Macklem PT. Bronchial hyporesponsiveness. Chest 87: 158S159S,
ging of the segmental, subsegmental, and smaller conducting 1985.
airways that leads to hyperination but not destruction of 15. Cudkowicz L. The Human Bronchial Circulation in Health and
the parenchyma. These airway plugs are a manifestation of Disease. . Baltimore: Williams & Wilkins, 1968.
the uid and cellular exudative phase of an inammatory 16. Hill P, Goulding D, Webber SE, Widdicombe JG. Blood sinuses in the
process based in the airway tissue (Fig. 6.6). The cytokine submucosa of the large airways of sheep. J Anat 162: 23547, 1989.
and cellular content of this process is consistent with a Th- 17. Hogg JC, Chu F, Utokaparch S et al. The nature of small-airway
2 type of immune response [36, 37], and quantitative post- obstruction in chronic obstructive pulmonary disease. N Engl J Med
mortem studies have established that the airway occlusion 350: 264553, 2004.
18. van der Strate BW, Postma DS, Brandsma CA et al. Cigarette smoke-
by plugs of this exudate is the major determinant of death
induced emphysema: A role for the B cell?. Am J Respir Crit Care Med
from asthma [48]. 173: 75158, 2006, Epub 2006 Jan 6.
19. Elliot JG, Jensen CM, Mutavdzic S, Lamb JP, Carroll NG, James AL.
COPD Aggregations of lymphoid cells in the airways of nonsmokers, smokers,
The chronic bronchitis of COPD is dened by excess cough and subjects with asthma. Am J Respir Crit Care Med 169: 71218, 2004.
with sputum production and is associated with an inam- 20. Rigler LG, Koucky R. Roentgen studies of pathological physiology of
bronchial asthma. Am J Roentgenol 39: 35362, 1938.
matory process located in the mucosa, gland ducts, and
21. Huber HL, Koessler KK. The pathology of bronchial asthma. Arch
glands of intermediate-sized bronchi between 2 and 4 mm Intern Med 30: 689760, 1922.
internal diameter. The airway obstruction in COPD is the 22. Cardell BS, Pearson RSB. Death in asthmatics. Thorax 14: 34152, 1959.
result of a similar inammatory response in the smaller 23. Earle BV. Fatal bronchial asthma: A series of 15 cases with a review of
bronchi and bronchioles under 2 mm internal diameter, the literature. Thorax 8: 195206, 1953.
where the repair process associated with chronic inam- 24. Houston JC, de Navasquez S, Trounce JR. A clinical and pathological
mation thickens the airway wall and narrows the lumen to study of fatal cases of status asthmaticus. Thorax 8: 20713, 1953.
cause xed airway obstruction. Emphysematous destruction 25. Dunnill MS, Massarella GR, Anderson JA. A comparison of the
of the lung surface contributes to the decline in FEV1 by quantitative anatomy of the bronchi in normal subjects, in status asth-
reducing the elastic recoil force available to drive air out of maticus, in chronic bronchitis and in emphysema. Thorax 24: 17679,
1969.
the lung and is responsible for reduced gas exchange. The
26. MacDonald IG. The local and constitutional pathology of bronchial
acute exacerbations of COPD that occur with increas- asthma. Ann Intern Med 6: 25377, 1933.
ing frequency as the disease progresses have several known 27. Messer J, Peters GA, Bennet WA. Cause of death and pathological
causes including infection, right heart failure, and pulmo- ndings in 304 cases of bronchial asthma. Dis Chest 38: 61624, 1960.
nary embolism but it is discouraging that in up to 25% of 28. Richards W, Patrick JR. Death from asthma in children. Am J Dis Child
cases admitted to hospital the cause is unknown. 110: 421, 1965.

79
Asthma and COPD: Basic Mechanisms and Clinical Management

29. Saetta M, di Stefano A, Rosina C, Thiene G, Fabbri LM. Quantitative relationship of CD-8  T lymphocytes with FEV1. Am J Respir Crit
structural analysis of peripheral airways and arteries in sudden fatal Care Med 155: 38287, 1997.
asthma. Am Rev Respir Dis 143: 13843, 1991. 56. Saetta M, Di Stefano A, Turato G et al. T lymphocytes in the periph-
30. Florey H. The secretion of mucus and inammation in mucus mem- eral airways of smokers with chronic obstructive pulmonary disease.
branes. In: Florey H (ed.), General Pathology, 3rd edn, pp. 16796. Am J Respir Crit Care Med 157: 82226, 1998.
London: Lloyd-Luke Medical Books, 1962. 57. Thurlbeck WM, Angus GE. The distribution curve for chronic bron-
31. Ciba Symposium on the Identication of Asthma. January 1971. chitis. Thorax 19: 43642, 1964.
32. Djukanovic R, Wilson JW, Lai CKW, Holgate ST, Howarth PH. The 58. Jamal K, Cooney TP, Fleetham JA, Thurlbeck WM. Chronic bronchi-
safety aspects of beroptic bronchoscopy, bronchoalveolar lavage, and tis: Correlation of morphological ndings and sputum production and
endobronchial biopsy in asthma. Am Rev Respir Dis 143: 77277, 1991. ow rates. Am J Respir Dis 129: 71922, 1984.
33. Djukanovic R, Roche WR, Wilson JW et al. Mucosal inammation in 59. Carlile A, Edwards C. Structural variations in the main bronchi of the
asthma. Am Rev Respir Dis 142: 43457, 1990. left lung: a morphometric study. Br J Dis Chest 77: 34448, 1983.
34. Glynn AA, Michaels L. Bronchial biopsy in chronic bronchitis and 60. Mackenzie HI, Outhred KG. Chronic bronchitis in coal miners:
asthma. Thorax 15: 14253, 1960. Antimortem/postmortem comparisons. Thorax 24: 52735, 1969.
35. Mosmann TR, Coman RL. TH1 and TH2 cells: Dierent patterns 61. Haraguchi M, Shemura S, Shirata K. Morphologic analysis of bron-
of lymphokine secretion lead to dierent functional properties. Annu chial cartilage in chronic obstructive pulmonary disease and bronchial
Rev Immunol 7: 14573, 1989. asthma. Am J Respir Crit Care Med 159: 100513, 1999.
36. Robinson DS, Hamid Q, Ying S et al. Predominant TH2-like bron- 62. Thurlbeck WM, Pun R, Toth J, Fraser RG. Bronchial cartilage in
choalveolar T-lymphocyte population in atopic asthma. N Engl J Med chronic obstructive lung disease. Am Rev Respir Dis 109: 7380, 1974.
326: 298304, 1992. 63. van Braband T, Cauberghs M, Verbeken E et al J Appl Physiol: Respir.
37. Hamid Q, Song Y, Kotsimbos TC et al. Small airways inammation in Environ. Exercise Physiol. 55: 173342, 1983.
asthma. J Allergy Clin Immunol 100: 4451, 1997. 64. Dayman H. Mechanics of airow in health and emphysema. J Clin
38. Friedman BJ. Functional anatomy of the bronchi. Bull Pathophysiol Invest 3031: 117590, 1951.
Respir 8: 54551, 1972. 65. Butler J, Caro C, Alkaler R, Dubois AB. Physiological factors aecting
39. Moreno R, Hogg JC, Par PD. Mechanics of airway narrowing. Am airway resistance in normal subjects and in patients with obstructive
Rev Respir Dis 133: 117180, 1986. airways disease. J Clin Invest 39: 58491, 1960.
40. James AL, Par PD, Hogg JC. The mechanics of airway narrowing in 66. Mead J, Turner JM, Macklem PT, Little J. Signicance of the relation-
asthma. Am Rev Respir Dis 139: 24246, 1989. ship between lung recoil and maximum expiratory ow. J Appl Physiol
41. Wiggs BR, Moreno R, Hogg JC, Hilliam C, Par PD. A model of the 22: 95108, 1967.
mechanics of airway narrowing. J Appl Physiol 69: 84960, 1990. 67. Matsuba K, Thurlbeck WM. The number and dimensions of small air-
42. Wiggs BR, Bosken C, Par PD, James A, Hogg JC. A model of air- ways in emphysematous lungs. Am J Pathol 67: 26575, 1972.
way narrowing in asthma and chronic obstructive pulmonary disease. 68. Hogg JC, Chu FS, Tan WC et al. Survival following lung volume
Am Rev Respir Dis 145: 125158, 1992. reduction in COPD: Insights from small airway pathology. Am J Respir
43. Woolcock AJ, Salome CM, Yan K. The shape of the dose-response Crit Care Med 16, 2007.
curve to histamine in asthmatic and normal subjects. Am Rev Respir 69. McLean KA. Pathogenesis of pulmonary emphysema. Am J Med 25:
Dis 130: 7175, 1984. 6274, 1958.
44. Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Site of airway 70. Niewoehner DE, Kleinerman J, Reisst DB. Pathologic changes in
obstruction in pulmonary disease: Direct measurements of intrabron- the peripheral airways of young cigarette smokers. N Engl J Med 291:
chial pressure. J Appl Physiol 72: 101623, 1992. 75558, 1974.
45. Lambert R. The role of the bronchial basement membrane and airway 71. Auerbach O, Garnkle L, Hammond EC. Relation of smoking and
collapse. J Appl Physiol 71: 66673, 1991. age to ndings in lung parenchyma: A microscopic study. Chest 65:
46. Wiggs BR, Hrousis CA, Drazen JM, Kamm RD. The implications of 2935, 1974.
airway wall buckling in asthmatic airways. Am J Respir Crit Care Med 72. Auerbach O, Hammond EC, Garnkle L, Benante C. Relation of
149: A585, 1994. smoking and age to emphysema: Whole lung section study. N Engl J
47. Macklem PT, Proctor DF, Hogg JC. The stability of peripheral airways. Med 286: 85357, 1972.
Respir. Physiol. 8: 191203, 1970. 73. Petty TL, Silverds GW, Stanford RE, Baird ME, Mitchell MS. Small
48. Kuyper LM, Par PD, Hogg JC, Lambert RK, Ionescu D, Woods R, airway pathology is related to increased closing capacity and abnor-
Bai TR. Characterization of airway plugging in fatal asthma. Am J Med mal slope of phase III in excised human lungs. Am Rev Respir Dis 121:
115: 611, 2003. 44956, 1980.
49. Mullen JBM, Wright JL, Wiggs B, Par PD, Hogg JC. Reassessment 74. Wright JL, Lawson LM, Par et al. Morphology of peripheral airways in
of inammation in the airways of chronic bronchitis. BMJ 291: 1235 current smokers and ex-smokers. Am Rev Respir Dis 127: 47477, 1983.
39, 1985. 75. Ollerenshaw SL, Woolcock AJ. Characteristics of the inammation in
50. Cosio M, Ghezzo M, Hogg JC et al. The relation between structural biopsies from large airways in subjects with asthma and chronic airow
changes in small airways and pulmonary function tests. N Engl J Med limitation. Am Rev Respir Dis 145: 92227, 1992.
298: 127781, 1978. 76. Gadek JE, Fells JA, Crystal RG. Cigarette smoking induces a func-
51. Retamales I, Elliott M, Meshi B et al. Amplication of inammation tional antiprotease deciency in the lower respiratory tract of humans.
in emphysema and its association with latent adenoviral infection. Science 206: 31516, 1979.
Am J Respir Crit Care Med 164: 46973, 2001. 77. Hunninghake GW, Crystal RG. Cigarette smoking and lung destruc-
52. Speizer FE, Tager IB. Epidemiology of chronic mucus hypersecretion tion: Accumulation of neutrophils in the lungs of cigarette smokers.
and obstructive airways disease. Epidemiol Rev 1: 12442, 1979. Am Rev Respir Dis 128: 83338, 1983.
53. Ciba Guest Symposium Report. Terminology, denitions and clas- 78. Stone DJ, Galor JD, McGowan SE et al. Functional 1-protease inhibitor
sications of chronic pulmonary emphysema and related conditions. in lower respiratory tract of cigarette smokers is not decreased. Science
Thorax 14: 28699, 1959. 221: 118789, 1983.
54. Reid L. Measurement of the bronchial mucous gland layer: A diagnos- 79. Snider GL, Kleinerman JL, Thurlbeck WM, Bengally ZH. Denition
tic yardstick in chronic bronchitis. Thorax 15: 13241, 1960. of emphysema. Report of a National Heart, Lung and Blood Institute,
55. OShaughnessy TC, Ansari TW, Barnes NC, Jeery PK. Inammation Division of Lung Disease Workshop. Am Rev Respir Dis 132: 18285,
in bronchial biopsies of subjects with chronic bronchitis: Inverse 1985.

80
Airway Pathology 6
80. Leopold JG, Goe J. Centrilobular form of hypertrophic emphysema 91. Lauria DB, Blumeneld HL, Ellis JT, Kilbourne ED, Rogers DE.
and its relation to chronic bronchitis. Thorax 12: 21935, 1957. Studies on inuenza in the pandemic of 195758. II: Pulmonary com-
81. Hogg JC, Macklem PT, Thurlbeck WM. The elastic properties of plication of inuenza. J Clin Invest 38: 21365, 1959.
the centrilobular emphysematous space. J Clin Invest 48: 130612, 1969. 92. Anthonisen NR, Manfreda J, Warren CP et al. Antibiotic therapy in
82. Anderson AE, Hernandez JA, Holmes WL, Foraker AG. Pulmonary exacerbations of COPD. Ann Intern Med 106: 196204, 1987.
emphysema: Prevalence, severity and anatomical patterns with respect 93. Monto AS, Higgins MW, Ross HW. The Tecumseh study of respira-
to smoking habits. Arch Environ Health 12: 56977, 1966. tory illness. VIII: Acute infection in chronic respiratory disease and
83. Pratt PC, Kilborn KH. A modern concept of emphysemas based on comparison groups. Am Rev Respir Dis 111: 2736, 1975.
correlations of structure and function. Hum Pathol 1: 44553, 1970. 94. Smith CB, Golden CA, Canner RE, Renzetti AD. Association of viral
84. Laurenzi GA, Toreno GM, Fishman AP. Bullous disease of the lung. and mycoplasmal pneumonia infections with acute respiratory illness
Am J Med 36: 36178, 1962. in patients with COPD. Am Rev Respir Dis 121: 22532, 1980.
85. McLean A, Warren PM, Gilooly M, Lamb D. Microscopic and mac- 95. Seemungal T, Harper-Owen R, Bhowmik A et al. Respiratory viruses,
roscopic measurements of emphysema: Relation to carbon monoxide symptoms, and inammatory markers in acute exacerbations and sta-
gas transfer. Thorax 47: 14449, 1992. ble chronic obstructive pulmonary disease. Am J Respir Crit Care Med
86. Connors AF, Dawson NV, Thomas C et al. Outcomes following acute 164(9): 161823, 2001.
exacerbation of severe chronic obstructive lung disease. Am J Respir Crit 96. Ko FW, Ip M, Chan PK et al. Viral etiology of acute exacerbations of
Care Med 154: 95967, 1996. chronic obstructive pulmonary disease in Hong Kong. Chest 15, 2007. ,
87. Stuart-Harris CH. The role of bacterial and viral infection in chronic Epub ahead of print
bronchitis. Arch Environ Health 16: 58695, 1968. 97. Tan WC, Xiang X, Qiu D, Ng TP, Lam SF, Hegele RG. Epidemiology
88. Stuart-Harris CH. Infection, the environment and chronic bronchitis. of respiratory viruses in patients hospitalized with near-fatal asthma,
J Roy Coll Physicians Lond 5: 35161, 1971. acute exacerbations of asthma, or chronic obstructive pulmonary dis-
89. Knipe DN. Virushost interactions. In: Fields BM, Knipe DN, ease. Am J Med 115(4): 27277, 2003.
Howley PM (eds). Fields Virology, pp. 27399. New York: Lippincott- 98. Saetta M, Di Stefano A, Maestrelli P et al. Airway eosinophilia in
Raven, 1996. chronic bronchitis during exacerbations. Am J Respir Crit Care Med
90. Hers JF, Masurel N, Mulder J. Bacteriology and histopathology of the 150: 164652, 1994.
respiratory tract in fatal Asian inuenza. Lancet ii: 114143, 1958.

81
Airway Remodeling
7
CHAPTER

Airway remodeling may be dened as a process of consequence of long-term airways disease, stud-
sustained disruption and modication of structural ies have revealed early manifestations in asth-
Stephen T. Holgate
cells and tissues leading to the development of a matics [7] and young smokers [8], suggesting School of Medicine, University of
new airway-wall structure and as a consequence, that remodeling maybe as much part of the pri- Southampton, Southampton, UK
new functions. Although this process was noted mary pathology of the disease rather than simply
as long ago as 1922 [1], interest in the underly- being a result of chronic inammation. However,
ing in asthma has risen only in recent years, the a considerable degree of variability in susceptibil-
debate about asthma causation largely being ity to remodel the changes exists in both patient
driven by concepts in immunology and inam- groups. Computerized tomography (CT) shows
mation. In chronic obstructive pulmonary disease increased airway wall thickening in proportion
(COPD), although airway structural changes are to disease severity in both children and adults
well recognized [2], the underlying pathogenesis with asthma [9, 10], whereas in highly labile
has received much less attention, possibly due to brittle asthma, this change is notably absent
the more peripheral location of pathology and the [11]. At a population level, asthma is associated
overshadowing interest in the adjacent emphyse- with a greater than normal decay in lung func-
matous tissue destruction. tion over time and associated loss of corticoster-
In both conditions, a number of remod- oid responsiveness [12]. In a small proportion of
eling processes occur; but in proportion, the asthma patients with severe chronic disease the
changes observed are quite dierent. Principal decline in lung function is more progressive and
among these changes are airway brosis, an ele- associated with persistence of symptoms despite
vation in smooth muscle mass, mucous meta- corticosteroid therapy, thereby resembling a
plasia, and glandular hypertrophy, in addition COPD-like state [13], although the pathology
to less well dened alterations of the bronchial that underlies this in the two disorders diers
vasculature and nerves to create an abnormal [14], The accelerated decline in lung function in
airway wall. In asthma, segmental and subseg- asthma may reect not only the presence of air-
mental bronchial walls are thickened over their way structural modication, but also the inade-
entire size range [3]. In COPD, only the inner quacy of currently available treatments to modify
wall area of the large airways is convincingly the remodeling processes.
thicker [4]. The peripheral airways (2 mm Airway remodeling may have a number
diameter), normally devoid of either supporting of clinical consequences for both asthma and
cartilage or bronchial glands, are also conspicu- COPD. For example, bronchial hyperresponsive-
ously remodeled in COPD [5, 6]. ness has been postulated to be a function of the
physical eects of overall airway wall thickening,
in addition to airway inammation and smooth
NATURAL HISTORY AND CLINICAL muscle reactivity [15]. Of interest, however is
IMPORTANCE the inverse relationship between airway wall
thickening demonstrated by CT and by endo-
bronchial ultrasound and airway hyperrespon-
The natural history of remodeling is not well siveness [16, 17]. Individual remodeling changes,
understood. Though it is surmised to be a such as an increased smooth muscle bulk or an

83
Asthma and COPD: Basic Mechanisms and Clinical Management

enhanced mucus producing facility, have their own implica- are causally involved, with their eects being augmented
tions for both symptom severity and airway function. by the airway inammatory responses induced by these
agents. Thus, the generation of reactive oxygen species and
the products of inltrating inammatory cells including
arginine-rich eosinophilic proteins [29], mast cell tryptase
MECHANISMS OF REMODELING [30], neutrophil elastase, and metalloproteases derived from
eosinophils and mast cells [31, 32], neutrophils and macro-
phages all induce epithelial injury. The result in asthma is
Epithelial damage, airway inflammation, a fragile bronchial epithelium with weakening of junctional
and epithelial repair adhesion structures, whereas in COPD the epithelium pro-
liferates and thickens. Consequently, a feature of asthma is
Responses of the airway epithelial barrier to injury and the shedding of columnar epithelial cells from their basal
manipulation and abnormalities in the ensuing processes cell attachments [3336]. In COPD, although atrophy and
of repair are the most likely causes of remodeling. In both shedding of the epithelium may occur [37], focal squamous
adult and children with chronic asthma, there is a good metaplasia is much more common [38, 39].
evidence that following repeated epithelial injury by envi- Altered airway adhesion molecule expression, a hall-
ronmental factors (e.g. allergens, viruses, and pollutants) mark of an active repair process, has been demonstrated in
the repair processes involve intercellular signaling between asthma and COPD. This includes enhanced expression of
the damaged and regenerating epithelium and the underly- CD44 [40], the integrins [41], and E cadherin [42] in asthma,
ing subepithelial (myo)broblast sheet, to inuence matrix while in both asthma and COPD there is augmented expres-
synthesis and the mass and composition of structures lying sion of ICAM-1 [43]. A recent important nding in asthma
beneath [18]. Under these conditions, the asthmatic airway is the incomplete formation of tight junctions at the apex of
is behaving like a chronic wound with release of proinam- the columnar epithelial cells which is preserved in tissue cul-
matory cytokines and multiple growth factors leading to ture of dierentiated asthmatic epithelium many weeks after
some permanent changes to airway wall morphology. These removal from the patients airways [44, 45] (Fig. 7.1).
epithelialmesenchymal interactions have invited parallels Since tight junctions are crucial in controlling para-
with the intercellular communication found during branch- cellular transport, their disruption in asthma could help to
ing morphogenesis, and remodeling has been suggested to explain why inhaled allergens and other inhaled environ-
reect a reactivation of these early life processes (discussed mental agents initiate and maintain a chronic inammatory
later). response at this site. Epithelial expression of the epidermal
In contrast to asthma, COPD is thought to be due growth factor receptor (EGFR) family is also increased
almost exclusively to the toxic eects of tobacco smoke. in asthma, and reects an injury and repair response seen
Repetitive attempts by the epithelium to protect itself and in other epithelial tissues by interacting with six distinct
repair the injury induced by this noxious agent leads to ligands:
marked structural changes to the epithelium with thickening
and squamous metaplasia accompanied by an enhanced epidermal growth factor (EGF)
mesenchymal response at some sites and alveolar destruc- transforming growth factor (TGF-)
tion at others. The airway obstruction that accompanies amphiregulin (AR)
these changes is resistant to corticosteroids and in this
respect becomes permanent or xed. heparin-binding EGF-like growth factor (HB-EGF)
The importance of airway inammation, integral and betacellulin (BTC)
intimately linked to the process of epithelial injury, is rec-
epiregulin.
ognized in both diseases [19]. In asthma, much interest has
focused on the CD4 T-lymphocyte that is skewed toward Activation of the EGFR promotes both migration
a Th2 type phenotype as the orchestrator of an immune and proliferation of epithelial cells [46], and there is in vitro
response to allergens [20]. The predominant pattern of Th2 and in vivo evidence supporting a role for this receptor in
cytokine expression results in an inammatory phenotype bronchial epithelial repair [47, 48]. However, in asthma,
where eosinophils and mast cells are prominent, but macro- increased EGFR expression does not appear to be coupled
phages, broblasts, and dendritic cells are also involved [21]. to an appropriate proliferative response by the repairing
The inammatory milieu diers considerably in COPD. epithelium [49]. This impairment may explain why EGFR
Eosinophils may play a role in a subset that has features in expression, as a marker of tissue injury, correlates positively
common with asthma and also during acute exacerbations with both asthma severity, neutrophil inux [50], and the
[22, 23], but their signicance in the majority is outweighed extent of subepithelial brosis [51]. The impaired epithelial
by the contribution of macrophages and neutrophils with repair response in asthma may be well linked to the actions
a CD8 T-cell preponderance [2426]. Indeed CD8 of the probrogenic transforming growth factor beta
T-cells are assuming increasing importance in orchestrating (TGF-) family of cytokines, which are known inhibitors
the neutrophil-mediated injury in COPD possibly linked of epithelial proliferation [52] and whose level is markedly
to chronic infection. Known perpetrators of epithelial dam- increased in asthmatic airways [53].
age in COPD include tobacco smoke toxins, viruses, and Although there are substantial changes in epithelial
bacteria, whereas in asthma house dust mite allergen [27], structure in COPD, relatively little is known of the factors
fungal and pollen enzymes [28], and toxic air pollutants driving this. Cigarette smoke results in enhanced EGFR

84
Airway Remodeling 7
(A)
Solutes

ZO-1 Actin
Occludin ZO-2
ZO-3
Claudins ZO-1

Cingulin
JAM
E-cadherin

Catenin

Cell 1 Cell 2

(B) Non-atopic normal Atopic asthma


XY

ZO-1

FIG. 7.1 Schematic representation


37.5 m 37.5 m of airway epithelial tight junction
showing their localisation at the apex
XZ of epithelial cells (A). Confocal images
of airway biopsies from atopic normal
ZO-1 and asthmatic subjects stained by
immunoflurescence for the tight junction
Nuclei protein ZO-1. Note the disrupted staining
25 m 25 m pattern in asthma (B).

expression in airways epithelium [54] and augmented basic broblast growth factor (FGF1)
expression of both EGF and TGF- have been observed in acidic broblast growth factor (FGF2)
subjects with chronic bronchitis [53]. Thus in both asthma
and COPD, there occurs a potential imbalance between insulin-like growth factor (IGF)
proliferative and anti-proliferative signaling in the air- platelet-derived growth factor (PDGF)
ways in the former leading to a frustrated and incomplete
response and in the latter an exuberant response. transforming growth factor (TGF-)
The relationship between epithelial injury and brosis Endothelin-1 (ET-1) [55].
has been examined using co-cultures of bronchial epithelial
cells and broblasts. In these studies, damage inicted on In addition to these, a range of other potentially
the epithelial cells that resulted in enhanced myobroblast important epithelial-derived products such as nerve growth
proliferation and collagen gene expression secondary to the factor (NGF), nitric oxide, metalloproteinases, bronectin,
release of a number of growth factors including (an extracellular matrix component with potent chemotactic

85
Asthma and COPD: Basic Mechanisms and Clinical Management

properties for broblasts [56]) and a range of proinamma- bronectin has been observed to cause selective recruitment
tory cytokines [5760] are produced by epithelial cells dur- of myobroblasts from a population of normal fetal lung
ing the repair process. broblasts [70]. In COPD, studies investigating the poten-
tial role of myobroblasts suggest an increase in peripheral
Remodeling of the extracellular matrix airways that show the greatest tendency to remodel [71].

The extracellular matrix is composed of a network of brous The role of growth factors and
and structural proteins embedded in a hydrated polysaccha-
ride gel to form the strong, resilient framework of the air- inflammatory mediators
way wall. Alteration in both the mass and the composition
of this structure is one of the primary aspects of remodeling The use of transgenic animal models of mediators over-
in both asthma and COPD, with enhanced broblast activ- expression has provided further evidence to link epithelial
ity being most directly responsible. growth factor and inammatory cytokine generation with
The repair environment in the airways produces a matrix remodeling. Specically, TGF-, over-expressed
number of changes in cytokine and growth factor expression in the rat airway epithelium by adenoviral gene transfer
to which the broblast is receptive. Studies in asthma have results in severe interstitial and pleural brosis [72], while
indicated that myobroblasts, a cell population with morpho- over-expression of TGF-, IL-6, or IL-11 as transgenes in
logical and biochemical features intermediate between those the airway epithelium induces subepithelial brosis in the
of broblasts and smooth muscle cells [61], are responsible lungs of mouse models [73, 74]. Mouse models expressing
for the particular pattern of matrix deposition in this disease. the Th2 cytokines IL-5 [75], IL-9 [76], and IL-13 [77] all
These cells, lying below and adjacent to the lamina reticularis developed remodeling responses in their airways, although
in a layer referred to as the attenuated broblast sheath are interestingly in mice over-expressing IL-4 the results are
major producers of collagen and proteoglycans implicated in inconsistent [78, 79]. Interleukin-13 is over-expressed in
matrix accumulation, as well as wound contraction [62]. In asthmatic airways [80] and is being pursued as an impor-
the absence of specic immunohistochemical markers for this tant new therapeutic target in asthma because of its involve-
cell type, myobroblasts are identied by ultrastructural cri- ment in B-cell IgE isotype switching, Th2 inammation,
teria and the expression of -smooth muscle actin (-SMA) mucous metaplasia and remodeling eects [81]. The TGF-
which is also found in abundance in smooth muscle cells. superfamily of cytokines (that include the bone morpho-
Though myobroblast hyperplasia has been demonstrated in genic proteins (BMPs)) are among the most studied with
the airway subepithelium in asthma [61, 63], with their num- respect to airway brosis and remodeling. TGF- is a mul-
bers correlating with the extent of subepithelial collagen thick- tifunctional probrotic growth factor and a key component
ness [63, 64], the signicance of this nding in relation to the in the regulation of tissue growth and dierentiation dur-
remodeling response involving the full thickness of the airway ing branching morphogenesis and wound repair as well as
wall is uncertain, however, their increased number is highly a promoting smooth muscle dierentiation [82]. It stimulates
characteristic of asthma. Myobroblasts (or bromyocyte as broblast growth and is responsible for the dierentiation
they have also been called) appear early after allergen chal- of broblasts into myobroblasts [55, 83, 84]. TGF- pro-
lenge, perhaps implying a quiescent precursor cell that dier- motes synthesis of extracellular matrix components by a
entiates to acquire myobroblast features [61]. Candidates for number of cells including broblasts, smooth muscle, epi-
this include broblasts, smooth muscle cells, or perhaps other thelial cells, and macrophages [85], and it blocks matrix
primitive mesenchymal or structural cells. Recent interest in degradation by inhibiting proteolytic enzyme synthesis and
the recruitment of CD32 bone marrow-derived brocytes augmenting the action of protease inhibitors with increased
from the circulation into the airways following allergen chal- expression both in asthma and COPD [53, 86, 87]. Tissue
lenge is another possible source of these cells [65]. A further macrophage TGF- production is elevated in both dis-
source of myobroblasts is through epithelialmesenchymal eases, while in asthma eosinophils and epithelial cells are
transition involving TGF- as described in pulmonary bro- also important sources [53, 88, 89], a signicant correla-
sis [66]. A number of factors have been identied which alter tion being demonstrated between the level of expression of
broblast -SMA expression: TGF- and the extent of subepithelial brosis and numbers
of broblasts [53]. TGF- levels in asthmatic airways are
TGF- [67] unaected by corticosteroid treatment.
Another growth factor cluster is platelet-derived
Heparin [68]
growth factor (PDGF). This is produced mainly in the air-
Interferon- ways by macrophages, epithelium, and most airway inam-
granulocyte macrophage colony stimulating factor matory cell types including mast cells and eosinophils
(GM-CSF). as important sources of in asthma [90, 91]. PDGF pro-
motes broblast chemotaxis, brosis, and smooth muscle
Proliferation and migration of resident progenitors mitogenesis [92] and would seem to be another very plau-
and/or myobroblasts already present in the airways may sible mediator of airway remodeling with asthmatic bron-
contribute to the increase in these cells beneath the epi- chial broblasts showing enhanced responsiveness [93].
thelium [63]. For example, smooth muscle mitogens and Nevertheless, it has been dicult to show increased expres-
broblast growth factors have been detected in bronchoal- sion of PDGF in the airways either in asthma or in COPD
veolar lavage (BAL) uid after allergen challenge [69], and [94, 95], so that its relevance in these diseases has yet to be

86
Airway Remodeling 7
clearly demonstrated. A family of probrotic mediators are muscle mitogen, is dependent on MMP3-induced cleav-
the endothelins (1 and 2) whose levels are increased in both age of its transmembrane precursor [42]. Mast cell tryptase,
diseases [9698]. These agents, in addition to their well acting via cellular protease activated receptor (PAR)2 acts
described vasoconstrictor and bronchoconstrictor proper- directly on broblasts and smooth muscle cells to promote
ties, the endothelins are potent activators of broblasts for both mitogenesis and collagen secretion [112] and is also
enhanced matrix production [99]. mitogenic for epithelialial cells and enhances probrogenic
Although in asthma epithelial EGFR expression has growth factor release [113].
been shown to correlate with the extent of subepithelial
brosis, the EGFR as an eector of matrix remodeling mes-
enchymal cells is also important, along with platelet-derived Effects of the altered matrix on remodeling
growth factor (PDGF), insulin-like growth factor, brob-
last growth factors and TGF-. Stimulation of broblast- The capacity of the extracellular matrix to directly and indi-
bound EGF and PDGF receptors works in concert with rectly inuence cell migration, proliferation, and matura-
binding of 1 integrins also present on the surface of these tion is indicative of a highly dynamic function in addition
cells by matrix components such as laminin or bronec- to provide structural support [85, 114]. Matrix components
tin to stimulate broblast chemotaxis and migration [100, such as decorin, versican, and bronectin provide stimuli
101]. Thus, alterations in growth factor and receptor expres- for inammatory, epithelial, and stromal cells by serving
sion, matrix composition, and adhesion molecule binding all as ligands for adhesion molecules [115] and by acting as a
have the potential to inuence broblast activity in the air- reservoir for release of cytokines, chemokines, and growth
way repair response. Although EGF immunoreactivity has factors such as TGF- [116]. Glycosaminoglycans, such as
been demonstrated in the airway mucosa of both asthmatic hyaluronic acid (HA), found to be increased in the BAL
and COPD patients, the number of EGF-expressing cells uid of asthmatics [117], facilitate cell migration, and pro-
did not correlate with either basement membrane thickness liferation during injury and repair, [118] by interacting with
or underlying broblast number [53]. Increased epithelial receptors such as CD44 [119], while survival of eosinophils
expression of TGF-, another ligand of the EGF family is prolonged by interaction with bronectin and laminin,
results in lung brosis, but the eect is mediated via the epi- which inhibit apoptosis in part through the autocrine eect
thelium to enhance other broblast growth factor secretion of GM-CSF [120]. Indeed, bronectin is a matrix glyco-
rather than through a direct action on broblasts [46]. protein that has received considerable attention regarding
its role in repair [85, 121]. It is produced by bronchial epi-
thelial cells [122] broblasts, smooth muscle cells, and mac-
The role of proteolytic enzymes rophages [123] and is upregulated by growth factors such
as TGF- [124] and integrin ligation [125]. Fibronectin is
Alteration in matrix turnover is a critical factor in the incorporated into the provisional matrix that forms after
remodeling process involving a range of proteolytic injury, where it acts as a chemoattractant for both epithelial
enzymes. Serine proteases and matrix metalloproteases that cells and broblasts [126]. Elevated quantities of bronectin
are produced by a variety of inammatory and stromal cells have been detected in bronchial lavage uid in COPD and
can digest all the major components of the extracellular in asthma where it is also found abnormally deposited in
matrix [102]. Examples include MMP3 (stromolysin) and the subbasement membrane along with tenascin C, another
MMP9 in asthma [103] [104] and MMP1, MMP9, and matrix glycoprotein that is chemotactic for leukocytes and
MMP12 in COPD (with regard to their potential to induce repair cells [63, 127, 128].
emphysema) [105, 106]. In emphysema it is believed that a
protease/anti-protease imbalance exists favoring the exces-
sive proteolytic digestion of lung parenchyma and especially
elastin, although there is now strong evidence that deposi- RESULTS OF MATRIX REMODELING IN
tion of new matrix is an equally important component of
COPD involving the more peripheral airways and contrib-
ASTHMA AND COPD
uting to increased airway stiness [107]. Thus, although
both MMP9 and neutrophil elastase levels are elevated in The pattern and distribution of matrix deposition in the
induced sputum of asthmatic and COPD patients, the aug- remodeled airway diers between asthma and COPD.
mented presence of these proteases is outweighed by a pro- Interest in asthma has centered mainly on the larger air-
portionally larger increase in their natural inhibitors TIMP1 ways, whereas in COPD it is involvement of small air-
and 1-antitrypsin [108, 109] which would favor brosis. ways where remodeling dominates the pathology. Matrix
The release of growth factors that are encrypted in remodeling may be roughly subdivided into thickening of
the extracellular matrix or from their cell membrane-bound the subepithelial basement membrane (lamina reticularis or
precursors is another way that proteases may contribute to basal lamina), submucosal thickening, matrix deposition in
remodeling. For example, both FGF and TGF- are bound airway smooth muscle and new matrix deposited in the air-
as inactive forms to heparan sulfate and decorin respec- way adventitia outside the smooth muscle layer. In addition,
tively [110, 111] and can be released from these matrix the proliferation of new blood vessels, nerves, and muscle as
stores by the proteolytic activity of plasmin and MMPs. well as mucous metaplasia and formation of larger and more
In contrast, release of heparin-binding EGF (hb-EGF), a numerous submucous glands are all part of the remodeling
further member of the EGF family and a potent smooth response.

87
Asthma and COPD: Basic Mechanisms and Clinical Management

Subepithelial basement membrane matrix MUCOUS METAPLASIA


deposition in asthma and COPD
In normal lung, submucosal mucous glands and epithe-
Deposition of protein beneath the true epithelial basement
lial goblet cells are distributed throughout the cartilagen-
membrane is characteristic of asthma. Electron microscopic
ous airways in. In asthma and COPD, epithelial mucous
and immunohistochemical analysis of bronchial biopsy
metaplasia and hyperplasia occur with hypertrophy of the
specimens has shown that the true basement membrane,
submucosal gland mass. An increase in both the number
made up of the lamina rara and lamina densa, is normal in
and the size of mucus-secreting cells leads to enlargement
both size and composition and that the changes occur in
of these tracheobronchial glands in both diseases [146,
the lamina reticularis. In this region, abnormal deposition
147]; however, a variable degree of replacement of serous
of interstitial repair collagen subtypes I, III, and V takes
with mucous acini occurs in COPD, but not in asthma
place [129] in addition to non-collagenous matrix compo-
[148].
nents that include bronectin [129], laminin 2 [130], and
Epithelial mucous cell metaplasia is observed in
tenascin C [131]. Classical epithelial-derived membrane
both central and peripheral airways in asthma [149, 150]
subtypes, such as collagens IV and VII, are absent from
but there exists a substantial degree of individual vari-
this abnormal subepithelial matrix layer. Recent studies
ation. In those who have died due to asthma goblet cells
in asthma using the blocking anti-IL-5 monoclonal anti-
are found in the peripheral airways [151], compatible with
body, mepolizumab, have shown that depletion of IL-5 and
most asthma deaths occurring in association with exces-
partial depletion of airway eosinophils results in reduced
sive mucous occlusion of airways [152]. In COPD, mucous
immunostaining for tenascin C, lumican, and collagen III
metaplasia and hyperplasia are observed both centrally and
in the lamina reticularis [132], but, interestingly, this is not
peripherally [2, 153, 154] resulting in a more even distri-
paralleled by remission of asthma [133]. Similar eects on
bution of secretary cells throughout the airways. Thus, the
the matrix component of the late phase allergen response
smaller (400 m diameter) airways which are normally
have also been reported [134]. It is possible that more pro-
populated with very few goblet cells become important
longed anti-IL-5 treatment in more severe asthma might be
contributors to the excess mucous which characterizes this
more clinically eective since mepolizumab is highly eec-
disease [155, 156]. Indeed, the mucus produced in asthma
tive in eosinophilic oesophagitis and nasal polyposis [135].
and COPD is qualitatively and quantitatively abnormal
Studies of COPD have not revealed an equivalent to
with major alterations in its cellular and molecular compo-
the subepithelial brosis as observed in asthma, although in
sition. The elevated ratio of mucous/serous acini in COPD
post-transplant obliterative bronchiolitis, this change occurs
results in secretion of a more gel-like thicker mucus, which
secondary to epithelial damage, epithelial-mesenchymal
is also lacking in anti-proteases [157]. In severe asthma,
transition, and proliferation of myobroblasts [136, 137].
bronchial obstruction from mucus plugging occurs in both
Studies of COPD show reveal normal basement membrane
central and peripheral airways [151, 158]. In COPD, par-
thickness [37, 138], although in a subset of patients with
tial or complete occlusion of the small (2 mm diameter)
COPD who display overlap with the asthmatic phenotype
airways with mucous plugs is common [5]. In both diseases,
thickening of the lamina reticularis is apparent especially in
reduced levels of surfactant lining the small airways results
the presence of eosinophils [139]. These individuals, who
in increased surface tension, airway collapse, and diculty
have a BAL eosinophilia and signicant corticosteroid
in re-expansion [159].
reversibility, also show demonstrable basement membrane
Expression of mucin genes, which encode the mucin
thickening, but the composition remains unknown [140].
glycoproteins, is the principal factor governing the dif-
Further studies are needed to properly dene the clinical
ferentiation of epithelial cells into goblet cells [160]. Both
and pathological characteristics of this subgroup and any
environmental and host factors, acting on the epithelium,
overlap with late onset intrinsic asthma.
have been shown to stimulate mucin gene upregulation and
mucin secretion. Environmental factors include infectious
Diffuse matrix deposition in asthma agents [161] and environmental pollutants [162] while
and COPD host factors include inammatory mediators [163] and cell
degranulation products [164, 165]. Acrolein, a low molecu-
Studies evaluating matrix deposition deep to the lamina lar weight component of cigarette smoke, induces epithelial
reticularis in asthma have been few. An excess of collagen MUC5AC gene expression, and mucous metaplasia in rats
including types III and V have been found in large airway in vivo [166] ,while the Th2 cytokines IL-4, IL-9, and IL-13
samples by some investigators [141, 142], but not by others have been closely linked to both augmented mucin gene
[129, 143]. Other matrix proteins and proteoglycans found expression, particularly the MUC5AC and MUC2 genes,
in excess in this region in asthma include decorin, lumican, and goblet cell dierentiation both in vitro and in vivo
biglycan, versican, and bronectin [108]. Excess matrix dep- [167170].
osition in COPD has been identied predominantly in the A central role has been postulated for the neutrophil
peripheral, noncartilaginous airways (2 mm diameter) [39, in stimulation of airway mucin production. This is based
144]. However, one immunohistochemical investigation has on the observation of augmented MUC5AC expression
demonstrated reduced decorin and biglycan in the periph- by cultured epithelium when exposed to neutrophils [171],
eral airways, with staining patterns for type IV collagen and possibly through neutrophil elastase and oxidative stress,
laminin similar to those observed in control lungs [145]. each of which has been shown to augment both epithelial

88
Airway Remodeling 7
MUC5AC mRNA and protein expression [171174]. The An extensive list of smooth muscle mitogens has been
EGFR is involved in regulation of airway mucin synthesis identied:
[175, 176] as mucin gene expression results from ligand- inammatory mediators
independent transactivation of the EGFR in response to
oxidative stress [177] that can be blocked by selective inhib- growth factors
itors of the EGFR tyrosine kinase [131]. Both EGF and enzymes
EGFR expression are elevated in bronchial glandular tissue
in asthmatic subjects compared with controls [178] sug- components of the extracellular matrix [192].
gesting a similar role for the EGFR in asthma. IL-13 may Group 1 are mediators, such as EGF and PDGF, which
cause induction of mucin gene expression via an EGFR- activate tyrosine kinase receptors. Group 2 includes those
dependent pathway. receptors coupled to GTP-binding proteins such as thrombin
and mast cell tryptase [193]. Although ET-1 and LTD4 are
smooth muscle mitogens in animal models, their eects on
human smooth is controversial, although recent studies sug-
SMOOTH MUSCLE REMODELING gest an interaction with tyrosine kinase receptors possibly
through the activation of metalloproteases and the mobiliza-
tion of growth factors such as EGF ligands from their cell-
The presence of an augmented airway smooth muscle bound precursors [193, 194]. TGF- and PDGF isoforms are
bulk in asthma and COPD is well established. In asthma, both dierentiation factors for airway smooth muscle, but at
smooth muscle mass is increased in both large [179] and the time of writing their role in smooth muscle development
peripheral [180, 181] airways, although debate contin- in asthmatic and COPD airways remains speculative.
ues over whether hypertrophy or hyperplasia dominate. A further association between inammation and
Autopsy studies suggest the existence of two distinct pat- smooth muscle function has been suggested by the
terns. The type 1 pattern has increased muscle mass due enhanced expression of adhesion molecules such as ICAM-
to hyperplasia restricted to large central airways, while in 1 and VCAM-1 on airway smooth muscle cells in response
type 2 there is smooth muscle thickening throughout the to TNF-, IL-1, LPS, and IFNs [195]. Furthermore,
bronchial tree caused predominantly by hypertrophy, par- the adherence of T-cells to smooth muscle cells results in
ticularly in the small airways, with a mild degree of hyper- stimulation of DNA synthesis [195]. The capacity of these
plasia in the larger airways [182]. The situation is further ASM to express adhesion molecules, synthesize ECM
complicated by the considerable degree of heterogeneity components, and release inammatory cytokines and chem-
present. An increase in smooth muscle mass is not always okines including RANTES [196], eotaxin, and IL-8 [192]
demonstrated in mild asthma [183] or in post-mortem indicates that smooth muscle remodeling may itself be part
studies of asthmatics whom have died from other causes of the inammatory process. Towards this end, there is now
[184]. Why dierent patterns of smooth muscle enlarge- good evidence that in asthma smooth muscle cells and their
ment should exist in asthma or what factors predispose associated matrix support a distinct mast cell population
some but not other asthmatics to the development of either that maybe highly relevant to the pathogenesis of hyperre-
one is unknown. Nor is it known whether smooth muscle sponsiveness [197, 198].
changes occur before, in parallel with or as a consequence In asthma and COPD, polymorphism of the dis-
of the inammation. integrin and metalloprotease 33 (ADAM33) molecule is
The peripheral airways are also the location of an strongly associated with BHR and an accelerated decline
increase in smooth muscle mass in COPD [183, 185187], in lung function over time [199, 200]. ADAM33 is local-
though it is suggested that the changes are less marked ized to airway smooth muscle and is implicated in vascu-
than those in asthma [183]. Studies often describe these logenesis through release of its soluble form [201]. There
changes under the heading of hypertrophy, but the extent to is also much interest in the factors that are chemotractant
which hyperplasia plays a role is again unclear. Estimates of for smooth muscle cells, their relationship to myobroblasts
smooth muscle enlargement in the larger airways in COPD and whether mechanisms for removal of muscle could be
have varied [188]. Some investigators have observed no therapeutically benecial. Towards this end, bronchoscopic
abnormality in smooth muscle area [179], while others thermoplasty is looking very promising as an entirely new
report up to a twofold increase in bronchial smooth muscle approach to asthma treatment [202, 203].
thickness attributable to both hyperplasia and hypertrophy
[189]. A clinical correlation with the presence of wheeze
has also been suggested [190].
The mechanisms leading to the increase in smooth
VASCULAR AND NEURAL ALTERATIONS
muscle in asthma (and COPD) are largely speculative and
include the growth promoting potential of an enriched Elevated airway-wall blood-vessel area has been demon-
plasma environment due to microvascular leakage [191]. strated in adult and childrens asthma and is greater than in
The mitogenic inuences of mediators involved in the controls or subjects with COPD [180, 183, 204]. However,
inammatory response and an intrinsic abnormality of it is unclear whether this vascular remodeling is prima-
smooth muscle itself. However, most knowledge of factors rily due to the formation of new blood vessels [205] or to
that promote smooth muscle growth has come from in vitro enlargement of the existing microvasculature. A study of
cell culture studies [192]. the membranous bronchioles of subjects with asthma and

89
Asthma and COPD: Basic Mechanisms and Clinical Management

COPD has suggested the latter [183]. Indeed fatal asthma inammation. Another possibility is that the structural
is known to be associated with dilatation of bronchial changes either precede or occur in parallel rather than
mucosal blood vessels, congestion, and wall edema [206]. sequential to inammation. While in vitro studies suggest
However, Li and Wilson [207] have discovered changes possible inhibitory eects of bronchodilator drugs such as
suggestive of new vessel formation in mild asthma, and the 2-adrenoceptor agonists and xanthines (e.g. theophyl-
microenvironment in asthma has been shown to possess the line) on smooth muscle and broblast proliferation [217,
potential for angiogenesis. 218], similar eects on these measures in vivo are far from
Mediators such as histamine, heparin, and tryptase all established.
possess angiogenic properties, while expression of vascular It has been proposed that a more eective strat-
endothelial growth factor (VEGF), a potent vascular growth egy to reduce airway smooth muscle in asthma would be
factor, is upregulated by agents such as TGF-, TNF-, and to interfere with growth factor and other receptor mecha-
TGF- that are involved in the inammatory milieu of the nisms. Suggested approaches include blocking the actions
asthmatic airway. Of particular importance is VEGF which of TGF- in an attempt to limit smooth muscle dieren-
is released from epithelial cells as well as a broad range of tiation as well as brosis. Monoclonal antibodies targeted
inammatory cells including mast cells. The pro-angiogenic to TGF- are in clinical trials in diuse brotic disorders
function of soluble ADAM33 is also relevant here. such as scleroderma, but concerns over safety have so far
There is evidence in severe asthma of increased air- prevented their exploration in asthma. The other functions
way neural networks. This is most likely the consequence of this growth factor such as the development of anti-
of nerve growth factor (and related neurotrophins) release inammatory T-regulatory cells need to be taken into
from epithelial and inammatory cells. Circulating levels account as possible alternative on target side eects [219].
of NGF relate [208] strongly to asthma severity and may Whether targeting other mechanisms such as thrombin
prove to be a useful biomarker of this more severe pheno- inhibitors, protease activated receptors themselves, endothe-
type [209]. In addition, in both asthma and COPD, the lin and its receptors and other growth factors such as PDGF
compromised epithelial barrier allows a greater exposure of are very much in the early experimental stage. So far, bron-
nerve endings to environmental stimuli. Thus, the poten- chial thermoplasty seems the most promising approach
tial for release of neurotransmitters such as the tachykinins although even with this, side eects of delayed airway
substance P and neurokinin A is increased. These agents, brosis is a concern. One exciting possibility, however, is
in addition to their eects on vascular and smooth muscle the inhibition of IL-13, a cytokine with multiple eects on
homeostasis, can contribute to local inammation with the inammation, remodeling, and mucous metaplasia. After
attraction and activation of inammatory cells. Neurogenic successfully pass in phase I safety studies, a number of
inammation is one way sensory information received human and humanized monoclonal antibodies targeting the
from the inhaled environment could contribute to ongoing IL-13 pathway are in clinical development in asthma. The
inammation, although this has been dicult to prove in clear advantage here is that blockade of this pathway may
asthma or COPD but is easily shown in animal models of inuence several interacting aspects of chronic asthma.
airway inammation [210]. Attempts are in progress to reduce mucus secretion.
While inhibiting EGFR signaling would be one route the
downstream consequences of this on epithelial tissue repair
responses would be serious, especially since epithelial repair
EFFECTS OF THERAPY in asthma is already known to be defective [220]. However,
the chloride channel Gob 5 (hCLCA1) as an IL-13 sen-
sitive mechanism that inuences the secretion of mucus,
Whether any of the current anti-inammatory strategies is a promising target for small molecular weight inhibitors
can signicantly alter the course of remodeling is unknown. [221].
Long-term corticosteroid therapy has been shown to slow A protective role for basement membrane thicken-
the annual rate of decline in lung function in adult asthmat- ing has been postulated also in restricting inammatory cell
ics [211]. However, other studies have suggested that a neg- passage to the epithelial layer above, while smooth muscle
ative relationship exists between response to treatment and hypertrophy may possibly help to maintain bronchiolar
duration of disease [212]. Added to this are reports showing caliber in severe emphysema [164]. Thus if a new anti-
persistent airow obstruction in some patients, despite both remodeling agent were to emerge, the benecial eects
oral and inhaled therapy [208]. The implication is that early would have to be weighed against the consequences of
therapy may, to a limited extent, prevent remodeling, but interfering with what may, in some ways, be a valuable
established structural change is steroid-insensitive. Several defence mechanism.
recent birth cohort studies [213, 214] in childhood asthma
have shown that inhaled corticosteroids modify asthma
symptoms while being continuously administered, but they
have little or no eect on the natural history of asthma.
Similar ndings have been reported in the large CAMP and
CONCLUDING COMMENTS
START inhaled corticosteroid intervention studies in older
asthmatic children [215, 216]. This is somewhat surpris- While airway wall remodeling undoubtedly occurs in both
ing if it is thought that airway remodeling and the increase asthma and COPD, its physiological signicance in health
in smooth muscle is the direct consequence of chronic and disease remains speculative. Of concern is the lack

90
Airway Remodeling 7
Increased susceptibility
of epithelium to damage by environmental
agents and inflammatory cell products

Epidermal growth factor

TGF-
PDGF
FGFs
IGFs
ET-1
VEGF
(Myo) fibroblasts

FIG. 7.2 Schematic representation of the


Blood vessels
epithelial mesenchymal trophic unit (EMTU)
in asthma that becomes reactivated with
the secretion of many growth factors by the
epithelium and underlying myofibroblasts
sheath.

of knowledge connecting inammation to the structural 7. Pohunek P. Eosinophilic inammation in the bronchial mucosa of chil-
changes. In asthma an overarching hypothesis is emerging dren with bronchial asthma. Eur Respir J 19(25), 1997.
that involves aberrant communication between a chroni- 8. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the
cally damaged epithelium and the underlying mesenchyme peripheral airways of young cigarette smokers. N Engl J Med 291(15):
75558, 1974.
reminiscent of reactivation of the epithelial mesenchymal
9. Vignola AM, Paganin F, Capieu L, Scichilone N, Bellia M, Maakel L
trophic unit (EMTU) involved in fetal branching morpho- et al. Airway remodelling assessed by sputum and high-resolution com-
genesis of the lung [222, 223] (Fig. 7.2). The inability of an puted tomography in asthma and COPD. Eur Respir J 24(6): 91017,
ecient epithelial wound healing response is responsible for 2004.
the production of a large number of growth factors impli- 10. De BJ, Scheinmann P. The use of imaging techniques for assessing
cated in brosis, vascuogenesis and new nerve formation, severe childhood asthma. J Allergy Clin Immunol 119(4): 80810, 2007.
but whether this process is also involved in smooth muscle 11. Boulet L, Belanger M, Carrier G. Airway responsiveness and
enhancement in asthma remains conjectural. The chronically bronchial-wall thickness in asthma with or without xed airow
damaged/repairing EMTU is also the source of a range of obstruction. Am J Respir Crit Care Med 152(3): 86571, 1995.
cytokines and growth factors to support chronic inamma- 12. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in
subjects with asthma. Eur J Respir Dis 70(3): 17179, 1987.
tion. Thus directing new therapies to increase resistance of
13. Brown PJ, Greville HW, Finucane KE. Asthma and irreversible airow
the asthmatic airways to environmental insults may create a obstruction. Thorax 39(2): 13136, 1984.
new approach to treatment. 14. Mauad T, Dolhniko M. Pathologic similarities and dierences
between asthma and chronic obstructive pulmonary disease. Curr Opin
Pulm Med 14(1): 3138, 2008.
References 15. Moreno RH, Hogg JC, Pare PD. Mechanics of airway narrowing.
Am Rev Respir Dis 133(6): 117180, 1986.
1. Huber H. The pathology of bronchial asthma. Arch Int Med 30: 16. Park JW, Hong YK, Kim CW, Kim DK, Choe KO, Hong CS. High-
689760, 1992. resolution computed tomography in patients with bronchial asthma:
2. Nagai A, West WW, Paul JL, Thurlbeck WM. The National Institutes Correlation with clinical features, pulmonary functions and bronchial
of Health Intermittent Positive-Pressure Breathing trial: Pathology hyperresponsiveness. J Investig Allergol Clin Immunol 7(3): 18692,
studies. I. Interrelationship between morphologic lesions. Am Rev 1997.
Respir Dis 132(5): 93745, 1985. 17. Shaw TJ, Wakely SL, Peebles CR, Mehta RL, Turner JM, Wilson SJ
3. James AL, Pare PD, Hogg JC. The mechanics of airway narrowing in et al. Endobronchial ultrasound to assess airway wall thickening:
asthma. Am Rev Respir Dis 139(1): 24246, 1989. Validation in vitro and in vivo. Eur Respir J 23(6): 81317, 2004.
4. Tiddens HA, Pare PD, Hogg JC, Hop WC, Lambert R, de Jongste JC. 18. Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE.
Cartilaginous airway dimensions and airow obstruction in human Epithelial-mesenchymal communication in the pathogenesis of chronic
lungs. Am J Respir Crit Care Med 152(1): 26066, 1995. asthma. Proc Am Thorac Soc 1(2): 9398, 2004.
5. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway 19. Jeery PK. Structural and inammatory changes in COPD: A com-
obstruction in chronic obstructive lung disease. N Engl J Med 278(25): parison with asthma. Thorax 53(2): 12936, 1998.
135560, 1968. 20. Holgate ST, Wilson JR, Howarth PH. New insights into airway
6. Macklem PT, Thurlbeck WM, Fraser RG. Chronic obstructive disease inammation by endobronchial biopsy. Am Rev Respir Dis 145(2 Pt 2):
of small airways. Ann Intern Med 74(2): 16777, 1971. S26, 1992.

91
Asthma and COPD: Basic Mechanisms and Clinical Management

21. Djukanovic R, Roche WR, Wilson JW, Beasley CR, Twentyman OP, 43. Vignola AM, Campbell AM, Chanez P, Bousquet J, Paul-Lacoste P,
Howarth RH et al. Mucosal inammation in asthma. Am Rev Respir Michel FB et al. HLA-DR and ICAM-1 expression on bronchial
Dis 142(2): 43457, 1990. epithelial cells in asthma and chronic bronchitis. Am Rev Respir Dis
22. Saha S, Brightling CE. Eosinophilic airway inammation in COPD. 148(3): 68994, 1993.
Int J Chron Obstruct Pulmon Dis 1(1): 3947, 2006. 44. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol
23. Chanez P, Vignola AM, OShaugnessy T, Enander I, Li D, Jeery PK 120(6): 123344, 2007.
et al. Corticosteroid reversibility in COPD is related to features of 45. de Boer WI,Sharma HS,Baelemans SM,Hoogsteden HC,Lambrecht BN,
asthma. Am J Respir Crit Care Med 155(5): 152934, 1997. Braunstahl GJ. Altered expression of epithelial junctional proteins in
24. Saetta M, Di SA, Maestrelli P, Ferraresso A, Drigo R, Potena A et al. atopic asthma: Possible role in inammation. Can J Physiol Pharmacol
Activated T-lymphocytes and macrophages in bronchial mucosa of sub- 86(3): :10512, 2008.
jects with chronic bronchitis. Am Rev Respir Dis 147(2): 3016, 1993. 46. Davies DE, Polosa R, Puddicombe SM, Richter A, Holgate ST.
25. Keatings VM, Collins PD, Scott DM, Barnes PJ. Dierences in The epidermal growth factor receptor and its ligand family: Their
interleukin-8 and tumor necrosis factor-alpha in induced sputum potential role in repair and remodelling in asthma. Allergy 54(8): 771
from patients with chronic obstructive pulmonary disease or asthma. 83, 1999.
Am J Respir Crit Care Med 153(2): 53034, 1996. 47. Madtes DK, Busby HK, Strandjord TP, Clark JG. Expression of trans-
26. OShaughnessy TC, Ansari TW, Barnes NC, Jeery PK. Inammation forming growth factor-alpha and epidermal growth factor receptor is
in bronchial biopsies of subjects with chronic bronchitis: Inverse rela- increased following bleomycin-induced lung injury in rats. Am J Respir
tionship of CD8 T lymphocytes with FEV1. Am J Respir Crit Care Cell Mol Biol 11(5): 54051, 1994.
Med 155(3): 85257, 1997. 48. Van Winkle LS, Isaac JM, Plopper CG. Distribution of epidermal
27. Herbert CA, King CM, Ring PC, Holgate ST, Stewart GA, Thompson PJ growth factor receptor and ligands during bronchiolar epithelial repair
et al. Augmentation of permeability in the bronchial epithelium by from naphthalene-induced Clara cell injury in the mouse. Am J Pathol
the house dust mite allergen Der p1. Am J Respir Cell Mol Biol 12(4): 151(2): 44359, 1997.
36978, 1995. 49. Demoly P, Simony-Lafontaine J, Chanez P, Pujol JL, Lequeux N,
28. Hassim Z, Maronese SE, Kumar RK. Injury to murine airway epithe- Michel FB et al. Cell proliferation in the bronchial mucosa of asthmat-
lial cells by pollen enzymes. Thorax 53(5): 36871, 1998. ics and chronic bronchitics. Am J Respir Crit Care Med 150(1): 21417,
29. Frigas E, Loegering DA, Gleich GJ. Cytotoxic eects of the guinea pig 1994.
eosinophil major basic protein on tracheal epithelium. Lab Invest 42(1): 50. Hamilton LM, Torres-Lozano C, Puddicombe SM, Richter A, Kimber I,
3543, 1980. Dearman RJ et al. The role of the epidermal growth factor receptor in
30. Redington AE, Polosa R, Walls AF, Howarth PH, Holgate ST. Role of sustaining neutrophil inammation in severe asthma. Clin Exp Allergy
mast cells and basophils in asthma. Chem Immunol 62: 2259, 1995. 33(2): 23340, 2003.
31. Shute JK, Parmar J, Holgate ST, Howarth PH. Urinary gly- 51. Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH,
cosaminoglycan levels are increased in acute severe asthmaa role for Holgate ST et al. Involvement of the epidermal growth factor receptor
eosinophil-derived gelatinase B? Int Arch Allergy Immunol 113(1-3): in epithelial repair in asthma. FASEB J 14(10): 136274, 2000.
36667, 1997. 52. Moses HL, Yang EY, Pietenpol JA. Regulation of epithelial prolifera-
32. Ohno I, Ohtani H, Nitta Y, Suzuki J, Hoshi H, Honma M et al. tion by TGF-beta. Ciba Found Symp 157: 6674, 1991.
Eosinophils as a source of matrix metalloproteinase-9 in asthmatic air- 53. Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A
way inammation. Am J Respir Cell Mol Biol 16(3): 21219, 1997. et al. Transforming growth factor-beta expression in mucosal biopsies in
33. Lackie PM. The impact of allergen on the airway epithelium. Clin Exp asthma and chronic bronchitis. Am J Respir Crit Care Med 156(2 Pt 1):
Allergy 27(12): 138386, 1997. 59199, 1997.
34. Ollerenshaw SL, Woolcock AJ. Characteristics of the inammation in 54. Barsky SH, Roth MD, Kleerup EC, Simmons M, Tashkin DP.
biopsies from large airways of subjects with asthma and subjects with Histopathologic and molecular alterations in bronchial epithelium in
chronic airow limitation. Am Rev Respir Dis 145(4 Pt 1): 92227, 1992. habitual smokers of marijuana, cocaine, and/or tobacco. J Natl Cancer
35. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of Inst 90(16): 1198205, 1998.
the airway epithelium and bronchial reactivity in patients with asthma. 55. Zhang S, Smartt H, Holgate ST, Roche WR. Growth factors secreted
Am Rev Respir Dis 131(4): 599606, 1985. by bronchial epithelial cells control myobroblast proliferation:
36. Jeery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial An in vitro co-culture model of airway remodeling in asthma. Lab
biopsies in asthma. An ultrastructural, quantitative study and correla- Invest 79(4): 395405, 1999.
tion with hyperreactivity. Am Rev Respir Dis 140(6): 174553, 1989. 56. Shoji S, Rickard KA, Ertl RF, Robbins RA, Linder J, Rennard SI.
37. Ollerenshaw SL, Woolcock AJ. Characteristics of the inammation in Bronchial epithelial cells produce lung broblast chemotactic factor:
biopsies from large airways of subjects with asthma and subjects with Fibronectin. Am J Respir Cell Mol Biol 1(1): 1320, 1989.
chronic airow limitation. Am Rev Respir Dis 145(4 Pt 1): 92227, 1992. 57. Cromwell O, Hamid Q, Corrigan CJ, Barkans J, Meng Q, Collins PD
38. Jeery PK. Structural and inammatory changes in COPD: A com- et al. Expression and generation of interleukin-8, IL-6 and granulocyte-
parison with asthma. Thorax 53(2): 12936, 1998. macrophage colony-stimulating factor by bronchial epithelial cells
39. Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J and enhancement by IL-1 beta and tumour necrosis factor-alpha.
et al. The relations between structural changes in small airways and Immunology 77(3): 33037, 1992.
pulmonary-function tests. N Engl J Med 298(23): 127781, 1978. 58. Laberge S, Ernst P, Ghaar O, Cruikshank WW, Kornfeld H, Center DM
40. Lackie PM, Baker JE, Gunthert U, Holgate ST. Expression of CD44 et al. Increased expression of interleukin-16 in bronchial mucosa of sub-
isoforms is increased in the airway epithelium of asthmatic subjects. jects with atopic asthma. Am J Respir Cell Mol Biol 17(2): 193202, 1997.
Am J Respir Cell Mol Biol 16(1): 1422, 1997. 59. Kwon OJ, Jose PJ, Robbins RA, Schall TJ, Williams TJ, Barnes PJ.
41. Peroni DG, Djukanovic R, Bradding P, Feather IH, Montefort S, Glucocorticoid inhibition of RANTES expression in human lung epi-
Howarth PH et al. Expression of CD44 and integrins in bronchial thelial cells. Am J Respir Cell Mol Biol 12(5): 48896, 1995.
mucosa of normal and mildly asthmatic subjects. Eur Respir J 9(11): 60. Aoki Y, Qiu D, Uyei A, Kao PN. Human airway epithelial cells express
223642, 1996. interleukin-2 in vitro. Am J Physiol 272(2 Pt 1): L27686, 1997.
42. Bullock GR. Expression of E-cadherin and alpha, beta and gamma 61. Gizycki MJ, Adelroth E, Rogers AV, OByrne PM, Jeery PK.
catenin is associated with epithelial shedding in human lung and nose. Myobroblast involvement in the allergen-induced late response in
J Clin Immunol 101(1 part 2): 36470, 1998. mild atopic asthma. Am J Respir Cell Mol Biol 16(6): 66473, 1997.

92
Airway Remodeling 7
62. Gabbiani G, Le LM, Bailey AJ, Bazin S, Delaunay A. Collagen 81. Izuhara K, Arima K, Kanaji S, Ohta S, Kanaji T. IL-13: A promis-
and myobroblasts of granulation tissue. A chemical, ultrastructural and ing therapeutic target for bronchial asthma. Curr Med Chem 13(19):
immunologic study. Virchows Arch B Cell Pathol 21(2): 13345, 1976. 229198, 2006.
63. Brewster CE, Howarth PH, Djukanovic R, Wilson J, Holgate ST, 82. Broide DH. Immunologic and inammatory mechanisms that drive
Roche WR. Myobroblasts and subepithelial brosis in bronchial asthma progression to remodeling. J Allergy Clin Immunol 121(3):
asthma. Am J Respir Cell Mol Biol 3(5): 50711, 1990. 56070, 2008.
64. Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S. Bronchial subepi- 83. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming
thelial brosis and expression of matrix metalloproteinase-9 in asthmatic growth factor-beta 1 induces alpha-smooth muscle actin expression
airway inammation. J Allergy Clin Immunol 102(5): 78388, 1998. in granulation tissue myobroblasts and in quiescent and growing
65. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identication cultured broblasts. J Cell Biol 122(1): 10311, 1993.
of circulating brocytes as precursors of bronchial myobroblasts in 84. Zhang HY, Gharaee-Kermani M, Zhang K, Karmiol S, Phan SH.
asthma. J Immunol 171(1): 38089, 2003. Lung broblast alpha-smooth muscle actin expression and contractile
66. Willis BC, duBois RM, Borok Z. Epithelial origin of myobroblasts phenotype in bleomycin-induced pulmonary brosis. Am J Pathol
during brosis in the lung. Proc Am Thorac Soc 3(4): 37782, 2006. 148(2): 52737, 1996.
67. Ronnov-Jessen L, Petersen OW. Induction of alpha-smooth muscle 85. Rennard SI. Repair mechanisms in asthma. J Allergy Clin Immunol
actin by transforming growth factor-beta 1 in quiescent human breast 98(6 Pt 2): S27886, 1996.
gland broblasts. Implications for myobroblast generation in breast 86. Rennard SI. Repair mechanisms in asthma. J Allergy Clin Immunol
neoplasia. Lab Invest 68(6): 696707, 1993. 98(6 Pt 2): S27886, 1996.
68. Desmouliere A, Rubbia-Brandt L, Grau G, Gabbiani G. Heparin 87. de Boer WI, van SA, Sont JK, Sharma HS, Stolk J, Hiemstra PS
induces alpha-smooth muscle actin expression in cultured broblasts et al. Transforming growth factor beta1 and recruitment of macro-
and in granulation tissue myobroblasts. Lab Invest 67(6): 71626, 1992. phages and mast cells in airways in chronic obstructive pulmonary
69. Naureckas ET, Ndukwu IM, Halayko AJ, Maxwell C, Hershenson MB, disease. Am J Respir Crit Care Med 158(6): 195157, 1998.
Solway J. Bronchoalveolar lavage uid from asthmatic subjects is 88. Minshall EM, Leung DY, Martin RJ, Song YL, Cameron L, Ernst P
mitogenic for human airway smooth muscle. Am J Respir Crit Care et al. Eosinophil-associated TGF-beta1 mRNA expression and air-
Med 160(6): 206266, 1999. ways brosis in bronchial asthma. Am J Respir Cell Mol Biol 17(3):
70. Kawamoto M, Matsunami T, Ertl RF, Fukuda Y, Ogawa M, Spurzem JR 32633, 1997.
et al. Selective migration of alpha-smooth muscle actin-positive myo- 89. Ohno I, Nitta Y, Yamauchi K, Hoshi H, Honma M, Woolley K et al.
broblasts toward bronectin in the Boydens blindwell chamber. Clin Transforming growth factor beta 1 (TGF beta 1) gene expression by
Sci (Lond) 93(4): 35562, 1997. eosinophils in asthmatic airway inammation. Am J Respir Cell Mol
71. Hogg JC, Pierce RA. Remodelling of peripheral lung tissue in COPD. Biol 15(3): 4049, 1996.
Eur Respir J 31(5): 91314, 2008. 90. Ohno I, Nitta Y, Yamauchi K, Hoshi H, Honma M, Woolley K
72. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector- et al. Eosinophils as a potential source of platelet-derived growth
mediated gene transfer of active transforming growth factor-beta1 factor B-chain (PDGF-B) in nasal polyposis and bronchial asthma.
induces prolonged severe brosis in rat lung. J Clin Invest 100(4): Am J Respir Cell Mol Biol 13(6): 63947, 1995.
76876, 1997. 91. Taylor IK, Sorooshian M, Wangoo A, Haynes AR, Kotecha S,
73. Tang W, Geba GP, Zheng T, Ray P, Homer RJ, Kuhn C III et al. Mitchell DM et al. Platelet-derived growth factor-beta mRNA in
Targeted expression of IL-11 in the murine airway causes lymphocytic human alveolar macrophages in vivo in asthma. Eur Respir J 7(11):
inammation, bronchial remodeling, and airways obstruction. J Clin 196672, 1994.
Invest 98(12): 284553, 1996. 92. Krymskaya VP, Homan R, Eszterhas A, Ciocca V, Panettieri RA Jr.
74. DiCosmo BF, Geba GP, Picarella D, Elias JA, Rankin JA, Stripp BR TGF-beta 1 modulates EGF-stimulated phosphatidylinositol 3-
et al. Airway epithelial cell expression of interleukin-6 in transgenic kinase activity in human airway smooth muscle cells. Am J Physiol
mice. Uncoupling of airway inammation and bronchial hyperreactivity. 273(6 Pt 1): L122027, 1997.
J Clin Invest 94(5): 202835, 1994. 93. Chanez P, Vignola M, Stenger R, Vic P, Michel FB, Bousquet J.
75. Lee JJ, McGarry MP, Farmer SC, Denzler KL, Larson KA, Carrigan PE Platelet-derived growth factor in asthma. Allergy 50(11): 87883,
et al. Interleukin-5 expression in the lung epithelium of transgenic 1995.
mice leads to pulmonary changes pathognomonic of asthma. J Exp 94. Chanez P, Vignola M, Stenger R, Vic P, Michel FB, Bousquet J.
Med 185(12): 214356, 1997. Platelet-derived growth factor in asthma. Allergy 50(11): 87883,
76. Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of inter- 1995.
leukin 9 in the lungs of transgenic mice causes airway inammation, 95. Aubert JD, Hayashi S, Hards J, Bai TR, Pare PD, Hogg JC. Platelet-
mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med derived growth factor and its receptor in lungs from patients with
188(7): 130720, 1998. asthma and chronic airow obstruction. Am J Physiol 266(6 Pt 1):
77. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J et al. L65563, 1994.
Pulmonary expression of interleukin-13 causes inammation, mucus 96. Springall DR, Howarth PH, Counihan H, Djukanovic R, Holgate
hypersecretion, subepithelial brosis, physiologic abnormalities, and ST, Polak JM. Endothelin immunoreactivity of airway epithelium in
eotaxin production. J Clin Invest 103(6): 77988, 1999. asthmatic patients. Lancet 337(8743): 697701, 1991.
78. Jain-Vora S, Wert SE, Temann UA, Rankin JA, Whitsett JA. Interleukin-4 97. Mattoli S, Soloperto M, Marini M, Fasoli A. Levels of endothelin in
alters epithelial cell dierentiation and surfactant homeostasis in the post- the bronchoalveolar lavage uid of patients with symptomatic asthma
natal mouse lung. Am J Respir Cell Mol Biol 17(5): 54151, 1997. and reversible airow obstruction. J Allergy Clin Immunol 88(3 Pt 1):
79. Rankin JA, Picarella DE, Geba GP, Temann UA, Prasad B, DiCosmo B 37684, 1991.
et al. Phenotypic and physiologic characterization of transgenic mice 98. Chalmers GW, MacLeod KJ, Sriram S, Thomson LJ, McSharry C,
expressing interleukin 4 in the lung: Lymphocytic and eosinophilic Stack BH et al. Sputum endothelin-1 is increased in cystic bro-
inammation without airway hyperreactivity. Proc Natl Acad Sci U S A sis and chronic obstructive pulmonary disease. Eur Respir J 13(6):
93(15): 782125, 1996. 128892, 1999.
80. Saha SK, Berry MA, Parker D, Siddiqui S, Morgan A, May R et al. 99. Takuwa Y, Yanagisawa M, Takuwa N, Masaki T. Endothelin, its
Increased sputum and bronchial biopsy IL-13 expression in severe diverse biological activities and mechanisms of action. Prog Growth
asthma. J Allergy Clin Immunol 121(3): 68591, 2008. Factor Res 1(4): 195206, 1989.

93
Asthma and COPD: Basic Mechanisms and Clinical Management

100. Li J, Lin ML, Wiepz GJ, Guadarrama AG, Bertics PJ. Integrin- 120. Anwar AR, Moqbel R, Walsh GM, Kay AB, Wardlaw AJ. Adhesion
mediated migration of murine B82L broblasts is dependent on the to bronectin prolongs eosinophil survival. J Exp Med 177(3): 83943,
expression of an intact epidermal growth factor receptor. J Biol Chem 1993.
274(16): 1120919, 1999. 121. Rennard SI. Inammation and repair processes in chronic obstructive
101. Sakai T, de la Pena JM, Mosher DF. Synergism among lysophos- pulmonary disease. Am J Respir Crit Care Med 160(5 Pt 2): S1216, 1999.
phatidic acid, beta1A integrins, and epidermal growth factor or 122. Shoji S, Ertl RF, Linder J, Romberger DJ, Rennard SI. Bronchial
platelet-derived growth factor in mediation of cell migration. J Biol epithelial cells produce chemotactic activity for bronchial epithelial
Chem 274(22): 1548086, 1999. cells. Possible role for bronectin in airway repair. Am Rev Respir Dis
102. OConnor CM, FitzGerald MX. Matrix metalloproteases and lung 141(1): 21825, 1990.
disease. Thorax 49(6): 6029, 1994. 123. Vignola AM, Chanez P, Chiappara G, Merendino A, Zinnanti
103. Ohno I, Ohtani H, Nitta Y, Suzuki J, Hoshi H, Honma M et al. E, Bousquet J et al. Release of transforming growth factor-beta
Eosinophils as a source of matrix metalloproteinase-9 in asthmatic air- (TGF-beta) and bronectin by alveolar macrophages in airway dis-
way inammation. Am J Respir Cell Mol Biol 16(3): 21219, 1997. eases. Clin Exp Immunol 106(1): 11419, 1996.
104. Dahlen B, Shute J, Howarth P. Immunohistochemical localisation of 124. Ignotz RA, Massague J. Transforming growth factor-beta stimulates
the matrix metalloproteinases MMP-3 and MMP-9 within the air- the expression of bronectin and collagen and their incorporation
ways in asthma. Thorax 54(7): 59096, 1999. into the extracellular matrix. J Biol Chem 261(9): 433745, 1986.
105. Finlay GA, ODriscoll LR, Russell KJ, DArcy EM, Masterson JB, 125. Zhang Q, Sakai T, Nowlen J, Hayashi I, Fassler R, Mosher DF.
FitzGerald MX et al. Matrix metalloproteinase expression and pro- Functional beta1-integrins release the suppression of bronectin
duction by alveolar macrophages in emphysema. Am J Respir Crit Care matrix assembly by vitronectin. J Biol Chem 274(1): 36875, 1999.
Med 156(1): 24047, 1997. 126. Shoji S, Ertl RF, Linder J, Romberger DJ, Rennard SI. Bronchial
106. Yoshioka A, Betsuyaku T, Nishimura M, Miyamoto K, Kondo T, epithelial cells produce chemotactic activity for bronchial epithelial
Kawakami Y. Excessive neutrophil elastase in bronchoalveolar lav- cells. Possible role for bronectin in airway repair. Am Rev Respir Dis
age uid in subclinical emphysema. Am J Respir Crit Care Med 152 141(1): 21825, 1990.
(6 Pt 1): 212732, 1995. 127. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial bro-
107. Kranenburg AR, Willems-Widyastuti A, Moori WJ, Sterk PJ, sis in the bronchi of asthmatics. Lancet 1(8637): 52024, 1989.
Alagappan VK, de Boer WI et al. Enhanced bronchial expression of 128. Trebaul A, Chan EK, Midwood KS. Regulation of broblast migra-
extracellular matrix proteins in chronic obstructive pulmonary disease. tion by tenascin-C. Biochem Soc Trans 35(Pt 4): 69597, 2007.
Am J Clin Pathol 126(5): 72535, 2006. 129. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial bro-
108. Vignola AM, Riccobono L, Mirabella A, Prota M, Chanez P, Bellia V sis in the bronchi of asthmatics. Lancet 1(8637): 52024, 1989.
et al.Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 130. Altraja A, Laitinen A, Virtanen I, Kampe M, Simonsson BG,
ratio correlates with airow obstruction in asthma and chronic bron- Karlsson SE et al. Expression of laminins in the airways in various
chitis. Am J Respir Crit Care Med 158(6): 194550, 1998. types of asthmatic patients: A morphometric study. Am J Respir Cell
109. Vignola AM, Bonanno A, Mirabella A, Riccobono L, Mirabella F, Mol Biol 15(4): 48288, 1996.
Prota M et al. Increased levels of elastase and alpha1-antitrypsin 131. Laitinen A, Altraja A, Kampe M, Linden M, Virtanen I, Laitinen LA.
in sputum of asthmatic patients. Am J Respir Crit Care Med 157(2): Tenascin is increased in airway basement membrane of asthmatics
50511, 1998. and decreased by an inhaled steroid. Am J Respir Crit Care Med 156(3
110. Redington AE, Roche WR, Holgate ST, Howarth PH. Co-localization Pt 1): 95158, 1997.
of immunoreactive transforming growth factor-beta 1 and decorin 132. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A,
in bronchial biopsies from asthmatic and normal subjects. J Pathol Ludwig MS et al. Anti-IL-5 treatment reduces deposition of ECM
186(4): 41015, 1998. proteins in the bronchial subepithelial basement membrane of mild
111. Ornitz DM. FGFs, heparan sulfate and FGFRs: Complex interac- atopic asthmatics. J Clin Invest 112(7): 102936, 2003.
tions essential for development. Bioessays 22(2): 10812, 2000. 133. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M,
112. Cairns JA, Walls AF. Mast cell tryptase stimulates the synthe- Brannick L et al. A study to evaluate safety and ecacy of mepoli-
sis of type I collagen in human lung broblasts. J Clin Invest 99(6): zumab in patients with moderate persistent asthma. Am J Respir Crit
131321, 1997. Care Med 176(11): 106271, 2007.
113. Cairns JA, Walls AF. Mast cell tryptase is a mitogen for epithe- 134. Phipps S, Flood-Page P, Menzies-Gow A, Ong YE, Kay AB.
lial cells. Stimulation of IL-8 production and intercellular adhesion Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and
molecule-1 expression. J Immunol 156(1): 27583, 1996. tenascin deposition in allergen-challenged human atopic skin. J Invest
114. Raghow R. The role of extracellular matrix in postinammatory Dermatol 122(6): 140612, 2004.
wound healing and brosis. FASEB J 8(11): 82331, 1994. 135. Stein ML, Collins MH, Villanueva JM, Kushner JP, Putnam PE,
115. Miyake K, Underhill CB, Lesley J, Kincade PW. Hyaluronate can Buckmeier BK et al. Anti-IL-5 (mepolizumab) therapy for eosi-
function as a cell adhesion molecule and CD44 participates in hyalur- nophilic esophagitis. J Allergy Clin Immunol 118(6): 131219, 2006.
onate recognition. J Exp Med 172(1): 6975, 1990. 136. Ward C, De SA, Fisher AJ, Pritchard G, Forrest I, Corris P.
116. Redington AE, Roche WR, Holgate ST, Howarth PH. Co-localization A descriptive study of small airway reticular basement membrane
of immunoreactive transforming growth factor-beta 1 and decorin thickening in clinically stable lung transplant recipients. J Heart Lung
in bronchial biopsies from asthmatic and normal subjects. J Pathol Transplant 24(5): 53337, 2005.
186(4): 41015, 1998. 137. Sato M, Liu M, Anraku M, Ogura T, DCruz G, Alman BA et al.
117. Bousquet J, Chanez P, Lacoste JY, Enander I, Venge P, Peterson C Allograft airway brosis in the pulmonary milieu: A disorder of tissue
et al. Indirect evidence of bronchial inammation assessed by titra- remodeling. Am J Transplant 8(3): 51728, 2008.
tion of inammatory mediators in BAL uid of patients with asthma. 138. Saetta M, Di SA, Maestrelli P, Ferraresso A, Drigo R, Potena A
J Allergy Clin Immunol 88(4): 64960, 1991. et al. Activated T-lymphocytes and macrophages in bronchial mucosa
118. Hamann KJ, Dowling TL, Neeley SP, Grant JA, Le AR. Hyaluronic of subjects with chronic bronchitis. Am Rev Respir Dis 147(2): 3016,
acid enhances cell proliferation during eosinopoiesis through the 1993.
CD44 surface antigen. J Immunol 154(8): 407380, 1995. 139. Jeery PK. Remodeling and inammation of bronchi in asthma
119. Rothenberg ME. CD44 A sticky target for asthma. J Clin Invest and chronic obstructive pulmonary disease. Proc Am Thorac Soc 1(3):
111(10): 146062, 2003. 17683, 2004.

94
Airway Remodeling 7
140. Chanez P, Vignola AM, OShaugnessy T, Enander I, Li D, Jeery PK 159. Nagai A, West WW, Thurlbeck WM. The National Institutes of
et al. Corticosteroid reversibility in COPD is related to features of Health Intermittent Positive-Pressure Breathing trial: Pathology
asthma. Am J Respir Crit Care Med 155(5): 152934, 1997. studies. II. Correlation between morphologic ndings, clinical nd-
141. Wilson JW, Li X. The measurement of reticular basement membrane ings, and evidence of expiratory air-ow obstruction. Am Rev Respir
and submucosal collagen in the asthmatic airway. Clin Exp Allergy Dis 132(5): 94653, 1985.
27(4): 36371, 1997. 160. Rogers DF. Airway goblet cells: Responsive and adaptable front-line
142. Chu HW, Halliday JL, Martin RJ, Leung DY, Szeer SJ, Wenzel SE. defenders. Eur Respir J 7(9): 1690706, 1994.
Collagen deposition in large airways may not dierentiate severe 161. Li JD, Feng W, Gallup M, Kim JH, Gum J, Kim Y et al.
asthma from milder forms of the disease. Am J Respir Crit Care Med Activation of NF-kappaB via a Src-dependent Ras-MAPK-pp90rsk
158(6): 193644, 1998. pathway is required for Pseudomonas aeruginosa-induced mucin
143. Godfrey RW, Lorimer S, Majumdar S, Adelroth E, Johnston PW, overproduction in epithelial cells. Proc Natl Acad Sci U S A 95(10):
Rogers AV et al. Airway and lung elastic bre is not reduced in 571823, 1998.
asthma nor in asthmatics following corticosteroid treatment. Eur 162. Borchers MT, Wert SE, Leikauf GD. Acrolein-induced MUC5ac
Respir J 8(6): 92227, 1995. expression in rat airways. Am J Physiol 274(4 Pt 1): L57381, 1998.
144. Adesina AM, Vallyathan V, McQuillen EN, Weaver SO, Craighead JE. 163. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W
Bronchiolar inammation and brosis associated with smoking. A et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic tar-
morphologic cross-sectional population analysis. Am Rev Respir Dis get in symptomatic corticosteroid dependent asthma. Thorax 60(12):
143(1): 14449, 1991. 101218, 2005.
145. van Straaten JF, Coers W, Noordhoek JA, Huitema S, Flipsen JT, 164. Breuer R, Christensen TG, Niles RM, Stone PJ, Snider GL. Human
Kauman HF et al. Proteoglycan changes in the extracellular matrix neutrophil elastase causes glycoconjugate release from the epithelial
of lung tissue from patients with pulmonary emphysema. Mod Pathol cell surface of hamster trachea in organ culture. Am Rev Respir Dis
12(7): 697705, 1999. 139(3): 77982, 1989.
146. Mitchell RS, Stanford RE, Johnson JM, Silvers GW, Dart G, George MS. 165. Kim KC, Wasano K, Niles RM, Schuster JE, Stone PJ, Brody JS.
The morphologic features of the bronchi, bronchioles, and alveoli in Human neutrophil elastase releases cell surface mucins from primary
chronic airway obstruction: A clinicopathologic study. Am Rev Respir cultures of hamster tracheal epithelial cells. Proc Natl Acad Sci U S A
Dis 114(1): 13745, 1976. 84(24): 93048, 1987.
147. Dunnill MS, Massarella GR, Anderson JA. A comparison of the 166. Borchers MT, Wert SE, Leikauf GD. Acrolein-induced MUC5ac
quantitative anatomy of the bronchi in normal subjects, in status expression in rat airways. Am J Physiol 274(4 Pt 1): L57381, 1998.
asthmaticus, in chronic bronchitis, and in emphysema. Thorax 24(2): 167. Temann UA, Prasad B, Gallup MW, Basbaum C, Ho SB, Flavell RA
17679, 1969. et al. A novel role for murine IL-4 in vivo: Induction of MUC5AC
148. Glynn AA, Michaels L. Bronchial biopsy in chronic bronchitis and gene expression and mucin hypersecretion. Am J Respir Cell Mol Biol
asthma. Istanbul Tip Fak Mecmuasi 15: 14253, 1960. 16(4): 47178, 1997.
149. Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima T. Marked goblet 168. Dabbagh K, Takeyama K, Lee HM, Ueki IF, Lausier JA, Nadel JA.
cell hyperplasia with mucus accumulation in the airways of patients who IL-4 induces mucin gene expression and goblet cell metaplasia in
died of severe acute asthma attack. Chest 101(4): 91621, 1992. vitro and in vivo. J Immunol 162(10): 623337, 1999.
150. Shimura S, Andoh Y, Haraguchi M, Shirato K. Continuity of airway 169. Louahed J, Toda M, Jen J, Hamid Q, Renauld JC, Levitt RC et al.
goblet cells and intraluminal mucus in the airways of patients with Interleukin-9 upregulates mucus expression in the airways. Am J
bronchial asthma. Eur Respir J 9(7): 1395401, 1996. Respir Cell Mol Biol 22(6): 64956, 2000.
151. Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima T. Marked 170. Zuhdi AM, Piazza FM, Selby DM, Letwin N, Huang L, Rose MC.
goblet cell hyperplasia with mucus accumulation in the airways Muc-5/5ac mucin messenger RNA and protein expression is a marker
of patients who died of severe acute asthma attack. Chest 101(4): of goblet cell metaplasia in murine airways. Am J Respir Cell Mol Biol
91621, 1992. 22(3): 25360, 2000.
152. Sheehan JK, Richardson PS, Fung DC, Howard M, Thornton DJ. 171. Takeyama K, Dabbagh K, Jeong SJ, Dao-Pick T, Ueki IF, Nadel JA.
Analysis of respiratory mucus glycoproteins in asthma: A detailed Oxidative stress causes mucin synthesis via transactivation of epider-
study from a patient who died in status asthmaticus. Am J Respir Cell mal growth factor receptor: Role of neutrophils. J Immunol 164(3):
Mol Biol 13(6): 74856, 1995. 154652, 2000.
153. Adesina AM, Vallyathan V, McQuillen EN, Weaver SO, Craighead JE. 172. Kim KC, Wasano K, Niles RM, Schuster JE, Stone PJ, Brody JS.
Bronchiolar inammation and brosis associated with smoking. Human neutrophil elastase releases cell surface mucins from primary
A morphologic cross-sectional population analysis. Am Rev Respir Dis cultures of hamster tracheal epithelial cells. Proc Natl Acad Sci U S A
143(1): 14449, 1991. 84(24): 93048, 1987.
154. Mitchell RS, Stanford RE, Johnson JM, Silvers GW, Dart G, 173. Voynow JA, Young LR, Wang Y, Horger T, Rose MC, Fischer BM.
George MS. The morphologic features of the bronchi, bronchioles, Neutrophil elastase increases MUC5AC mRNA and protein expression
and alveoli in chronic airway obstruction: A clinicopathologic study. in respiratory epithelial cells. Am J Physiol 276(5 Pt 1): L83543, 1999.
Am Rev Respir Dis 114(1): 13745, 1976. 174. Fischer B, Voynow J. Neutrophil elastase induces MUC5AC mes-
155. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the senger RNA expression by an oxidant-dependent mechanism. Chest
peripheral airways of young cigarette smokers. N Engl J Med 291(15): 117(5 Suppl 1): 317S320S, 2000.
75558, 1974. 175. Takeyama K, Dabbagh K, Lee HM, Agusti C, Lausier JA, Ueki IF
156. Cosio MG, Hale KA, Niewoehner DE. Morphologic and morpho- et al. Epidermal growth factor system regulates mucin production in
metric eects of prolonged cigarette smoking on the small airways. airways. Proc Natl Acad Sci U S A 96(6): 308186, 1999.
Am Rev Respir Dis 122(2): 22165, 1980. 176. Lee HM, Takeyama K, Dabbagh K, Lausier JA, Ueki IF, Nadel JA.
157. Kramps JA, Franken C, Meijer CJ, Dijkman JH. Localization of low Agarose plug instillation causes goblet cell metaplasia by activat-
molecular weight protease inhibitor in serous secretory cells of the ing EGF receptors in rat airways. Am J Physiol Lung Cell Mol Physiol
respiratory tract. J Histochem Cytochem 29(6): 71219, 1981. 278(1): L18592, 2000.
158. Kim KC, McCracken K, Lee BC, Shin CY, Jo MJ, Lee CJ et al. 177. Goldkorn T, Balaban N, Matsukuma K, Chea V, Gould R, Last J et al.
Airway goblet cell mucin: Its structure and regulation of secretion. EGF-Receptor phosphorylation and signaling are targeted by H2O2
Eur Respir J 10(11): 264449, 1997. redox stress. Am J Respir Cell Mol Biol 19(5): 78698, 1998.

95
Asthma and COPD: Basic Mechanisms and Clinical Management

178. Amishima M, Munakata M, Nasuhara Y, Sato A, Takahashi T, associated with accelerated lung function decline in asthma. Clin Exp
Homma Y et al. Expression of epidermal growth factor and epidermal Allergy 34(5): 75760, 2004.
growth factor receptor immunoreactivity in the asthmatic human air- 200. Gosman MM, Boezen HM, van Diemen CC, Snoeck-Stroband JB,
way. Am J Respir Crit Care Med 157(6 Pt 1): 190712, 1998. Lapperre TS, Hiemstra PS et al. A disintegrin and metalloprotease 33
179. Dunnill MS, Massarella GR, Anderson JA. A comparison of the quan- and chronic obstructive pulmonary disease pathophysiology. Thorax
titative anatomy of the bronchi in normal subjects, in status asthmaticus, 62(3): 24247, 2007.
in chronic bronchitis, and in emphysema. Thorax 24(2): 17679, 1969. 201. Puxeddu I, Pang YY, Harvey A, Haitchi HM, Nicholas B, Yoshisue H
180. Saetta M, Di SA, Rosina C, Thiene G, Fabbri LM. Quantitative et al. The soluble form of a disintegrin and metalloprotease 33 pro-
structural analysis of peripheral airways and arteries in sudden fatal motes angiogenesis: Implications for airway remodeling in asthma.
asthma. Am Rev Respir Dis 143(1): 13843, 1991. J Allergy Clin Immunol, 2008.
181. Carroll N, Elliot J, Morton A, James A. The structure of large and 202. Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC
small airways in nonfatal and fatal asthma. Am Rev Respir Dis 147(2): et al. Asthma control during the year after bronchial thermoplasty. N
40510, 1993. Engl J Med 356(13): 132737, 2007.
182. Ebina M, Takahashi T, Chiba T, Motomiya M. Cellular hypertro- 203. Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM
phy and hyperplasia of airway smooth muscles underlying bronchial et al. Safety and ecacy of bronchial thermoplasty in symptomatic,
asthma. A 3-D morphometric study. Am Rev Respir Dis 148(3): severe asthma. Am J Respir Crit Care Med 176(12): 118591, 2007.
72026, 1993. 204. Barbato A, Turato G, Baraldo S, Bazzan E, Calabrese F, Panizzolo C
183. Kuwano K, Bosken CH, Pare PD, Bai TR, Wiggs BR, Hogg JC. et al. Epithelial damage and angiogenesis in the airways of children
Small airways dimensions in asthma and in chronic obstructive pul- with asthma. Am J Respir Crit Care Med 174(9): 97581, 2006.
monary disease. Am Rev Respir Dis 148(5): 122025, 1993. 205. Battegay EJ. Angiogenesis: Mechanistic insights, neovascular diseases,
184. Sobonya RE. Quantitative structural alterations in long-standing and therapeutic prospects. J Mol Med 73(7): 33346, 1995.
allergic asthma. Am Rev Respir Dis 130(2): 28992, 1984. 206. Dunnill MS, Massarella GR, Anderson JA. A comparison of the
185. Mitchell RS, Stanford RE, Johnson JM, Silvers GW, Dart G, George quantitative anatomy of the bronchi in normal subjects, in status
MS. The morphologic features of the bronchi, bronchioles, and alve- asthmaticus, in chronic bronchitis, and in emphysema. Thorax 24(2):
oli in chronic airway obstruction: A clinicopathologic study. Am Rev 17679, 1969.
Respir Dis 114(1): 13745, 1976. 207. Li X, Wilson JW. Increased vascularity of the bronchial mucosa in
186. Cosio MG, Hale KA, Niewoehner DE. Morphologic and morpho- mild asthma. Am J Respir Crit Care Med 156(1): 22933, 1997.
metric eects of prolonged cigarette smoking on the small airways. 208. Backman KS, Greenberger PA, Patterson R. Airways obstruction in
Am Rev Respir Dis 122(2): 22165, 1980. patients with long-term asthma consistent with irreversible asthma.
187. Hale KA, Ewing SL, Gosnell BA, Niewoehner DE. Lung disease Chest 112(5): 123440, 1997.
in long-term cigarette smokers with and without chronic air-ow 209. Olgart HC, de BF, Oster JP, Duvernelle C, Kassel O, Pauli G et al.
obstruction. Am Rev Respir Dis 130(5): 71621, 1984. Nerve growth factor levels and localisation in human asthmatic bron-
188. Thurlbeck WM. Pathology of chronic airow obstruction. Chest 97 chi. Eur Respir J 20(5): 111016, 2002.
(2 Suppl): 6S10S, 1990. 210. Groneberg DA, Quarcoo D, Frossard N, Fischer A. Neurogenic
189. Hossain S, Heard BE. Hyperplasia of bronchial muscle in chronic mechanisms in bronchial inammatory diseases. Allergy 59(11):
bronchitis. J Pathol 101(2): 17184, 1970. 113952, 2004.
190. Takizawa T, Thurlbeck WM. Muscle and mucous gland size in the 211. Grol MH, Gerritsen J, Vonk JM, Schouten JP, Koeter GH, Rijcken B
major bronchi of patients with chronic bronchitis, asthma, and asth- et al. Risk factors for growth and decline of lung function in asthmatic
matic bronchitis. Am Rev Respir Dis 104(3): 33136, 1971. individuals up to age 42 years. A 30-year follow-up study. Am J Respir
191. Shiels IA, Bowler SD, Taylor SM. Airway smooth muscle prolif- Crit Care Med 160(6): 183037, 1999.
eration in asthma: The potential of vascular leakage to contribute to 212. Agertoft L, Pedersen S. Eects of long-term treatment with an
pathogenesis. Med Hypotheses 45(1): 3740, 1995. inhaled corticosteroid on growth and pulmonary function in asth-
192. Hirst SJ. Airway smooth muscle as a target in asthma. Clin Exp matic children. Respir Med 88(5): 37381, 1994.
Allergy 30(Suppl 1): 5459, 2000. 213. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ,
193. Panettieri RA Jr. Cellular and molecular mechanisms regulating air- Szeer SJ et al. Long-term inhaled corticosteroids in preschool chil-
way smooth muscle proliferation and cell adhesion molecule expres- dren at high risk for asthma. N Engl J Med 354(19): 198597, 2006.
sion. Am J Respir Crit Care Med 158(5 Pt 3): S13340, 1998. 214. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A.
194. Cohen MD, Ciocca V, Panettieri RA Jr. TGF-beta 1 modulates Secondary prevention of asthma by the use of Inhaled Fluticasone
human airway smooth-muscle cell proliferation induced by mitogens. propionate in Wheezy INfants (IFWIN): Double-blind, randomised,
Am J Respir Cell Mol Biol 16(1): 8590, 1997. controlled study. Lancet 368(9537): 75462, 2006.
195. Lazaar AL, Albelda SM, Pilewski JM, Brennan B, Pure E, 215. The Childhood Asthma Management Program Research Group.
Panettieri RA Jr. T lymphocytes adhere to airway smooth muscle Long-term eects of budesonide or nedocromil in children with
cells via integrins and CD44 and induce smooth muscle cell DNA asthma. N Engl J Med 343: 105463, 2000.
synthesis. J Exp Med 180(3): 80716, 1994. 216. Busse WW, Pedersen S, Pauwels RA, Tan WC, Chen YZ, Lamm CJ
196. John M, Hirst SJ, Jose PJ, Robichaud A, Berkman N, Witt C et al. et al. The Inhaled Steroid Treatment As Regular Therapy in Early
Human airway smooth muscle cells express and release RANTES in Asthma (START) study 5-year follow-up: Eectiveness of early
response to T helper 1 cytokines: Regulation by T helper 2 cytokines intervention with budesonide in mild persistent asthma. J Allergy Clin
and corticosteroids. J Immunol 158(4): 184147, 1997. Immunol 121(5): 116774, 2008.
197. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, 217. Tomlinson PR, Wilson JW, Stewart AG. Inhibition by salbutamol of
Pavord ID. Mast-cell inltration of airway smooth muscle in asthma. the proliferation of human airway smooth muscle cells grown in cul-
N Engl J Med 346(22): 1699705, 2002. ture. Br J Pharmacol 111(2): 64147, 1994.
198. Begueret H, Berger P, Vernejoux JM, Dubuisson L, Marthan R, 218. Levi-Schaer F, Touitou E. Xanthines inhibit 3T3 broblast prolif-
Tunon-de-Lara JM. Inammation of bronchial smooth muscle in eration. Skin Pharmacol 4(4): 28690, 1991.
allergic asthma. Thorax 62(1): 815, 2007. 219. Pyzik M, Piccirillo CA. TGF-beta1 modulates Foxp3 expression
199. Jongepier H, Boezen HM, Dijkstra A, Howard TD, Vonk JM, and regulatory activity in distinct CD4 T cell subsets. J Leukoc Biol
Koppelman GH et al. Polymorphisms of the ADAM33 gene are 82(2): 33546, 2007.

96
Airway Remodeling 7
220. Holgate ST. The airway epithelium is central to the pathogenesis of exposure of infant monkeys to allergen and/or ozone. Toxicol Appl
asthma. Allergol Int 57(1): 110, 2008. Pharmacol 214(3): 23743, 2006.
221. Long AJ, Sypek JP, Askew R, Fish SC, Mason LE, Williams CM 223. Holgate ST, Davies DE, Powell RM, Howarth PH, Haitchi HM,
et al. Gob-5 contributes to goblet cell hyperplasia and modulates pulmo- Holloway JW. Local genetic and environmental factors in asthma dis-
nary tissue inammation. Am J Respir Cell Mol Biol 35(3): 35765, 2006. ease pathogenesis: Chronicity and persistence mechanisms. Eur Respir
222. Joad JP, Kott KS, Bric JM, Peake JL, Plopper CG, Schelegle ES et al. J 29(4): 793803, 2007.
Structural and functional localization of airway eects from episodic

97
Asthma and COPD: Animal Models
8
CHAPTER

OVERVIEW are housed which eliminate many environmental Stephanie A. Shore1 and
modiers, and some dierences in the immune
system (mice have a more polarized T-lym- Steven D. Shapiro2
Animal models have been used extensively in phocyte response than humans). These dis- 1
Molecular and Integrative Physiological
the discovery of the biological processes that advantages have been documented elsewhere Sciences Program, Harvard School of
underlie asthma and COPD. For example, the [37] and may limit the utility of these mod- Public Health, Boston, MA, USA
demonstration by Gross et al. [1] that instilla- els for studying human disease in some cases. 2
Department of Medicine, University of
tion of papain into the lungs of rats resulted in a Mouse models of asthma and COPD will be
Pittsburgh, Pittsburgh, PA, USA
syndrome similar to emphysema, contributed to reviewed separately below.
the elastase/anti-elastase hypothesis regarding
the pathogenesis of emphysema. Animal mod-
els have also been used to guide research into
pharmacological interventions for the treatment
of asthma and COPD. For example, the current MOUSE MODELS OF ASTHMA
use of leukotriene receptor antagonists for the
treatment of asthma had its foundation partly Human asthma is characterized by intermittent
in the demonstration of the marked broncho- reversible airway obstruction, AHR, and airway
constrictor potency of cysteinyl leukotrienes in inammation. Pathologically, airway remodeling
guinea pigs [2]. While many species, including including increased airway smooth muscle mass,
dogs, cats, monkeys, horses, pigs, sheep, guinea subepithelial brosis, mucous hypersecretion,
pigs, and rats have been used to study asthma and increased airway vascularity are observed.
and COPD, most current investigations involve Asthma does not typically develop in most
the use of mice. Consequently, this review will non-human species. Consequently, many inves-
focus on models developed using this species. tigators have chosen to develop animal models
The advantages of using mice include cost of in which an asthma-like phenotype is induced
housing, a short breeding period, the availability by some intervention. The etiology of asthma is
of inbred species with known characteristics, a complex, and still poorly understood, and it is
well characterized immune system and genome, clear that multiple factors including exposure to
and the ability to either overexpress or delete allergens, exercise, exposure to air pollution, cer-
specic genes, sometimes conditionally, that is, tain viral infections, and the onset of obesity can
at specic times or in particular cells. This abil- also initiate symptoms. Because of the extensive
ity to genetically manipulate mice is a powerful nature of this topic, we have chosen to focus on
tool that permits very mechanistic experiments only two of these factors: allergen and obesity.
that cannot be accomplished in human subjects
and has yielded some important advances in our
understanding of lung disease. The disadvan- Modeling allergic asthma
tages of using mice include dierences in lung
anatomy, lung development, pattern and route Many investigators have used models of allergic
of breathing (mice are obligate nose breathers), asthma in which mice are rst sensitized to an
the pathogen-free facilities in which most mice allergen and then challenged with that allergen

99
Asthma and COPD: Basic Mechanisms and Clinical Management

via the lungs. The sensitization and the challenge protocols Murine models of allergic airways disease have been
vary widely among investigators, especially depending on used to examine the role of many cells, cytokines, chemok-
whether AHR or airway remodeling are being targeted. The ines, enzymes, and other factors in the pathology of asthma.
sensitization is usually i.p. injection of the allergen with an These studies are too numerous to document here. Instead,
adjuvant. Allergens used have included ovalbumin (OVA), we focus on three issues. One, the role of lymphocytes, can
picryl chloride, sheep erythrocytes, short ragweed extracts, be seen as a major success of these models. Two others, the
and house dust mite allergen. Although not environmen- role of IgE and mast cells, and the role of eosinophils are
tally very relevant, most investigators have used OVA as instances where the models do not appear to reproduce the
the allergen, perhaps because of its relatively low cost and human ndings.
easy availability. Mice are usually assessed 13 days after the Role of T-lymphocytes in allergen-induced airway
last of several daily airway challenges and the characteristics responses: A major accomplishment of studies using these
monitored are AHR, airway inammation, and serum IgE. murine models was in establishing a role for lymphocytes in
Consistent features of the model are increased OVA- the development of allergic asthma. For example, following
specic IgE and IgG1, eosinophilia (intraluminal, peribron- allergen sensitization and challenge, AHR does not develop
chial, and perivascular), and recruitment of lymphocytes to in athymic mice or in mice with severe combined immuno-
the airways. Increases in Th2-type cytokines either in bron- deciency, but adoptive transfer of lymphocytes from
choalveolar lavage (BAL) uid, in lung tissue, or in lymph wild-type sensitized and challenged mice restores AHR in
nodes draining the lungs also occur. These changes are gen- athymic mice [18, 19]. A particular role for CD4 T-lym-
erally similar to those observed in the airways of asthmatics phocytes was established by experiments demonstrating
after allergen challenge, although the kinetics of the recruit- that MHC Class II decient mice lacking mature CD4
ment of eosinophils and lymphocytes dier: in humans, the T-lymphocytes and mice depleted of CD4 T-cells do
peak in T-lymphocyte recruitment occurs about 24 h after not develop AHR or airway inammation following aller-
challenge and precedes the peak of eosinophil recruitment, gen sensitization and challenge [20, 21]. The requirement
whereas in mice, T-cell recruitment continues long after for CD4 T-cells was also underscored by the observation
eosinophils have peaked and returned to baseline [8]. that reconstitution of CD4 T-cells alone is sucient to
AHR is often, though not always observed in aller- restore allergen-induced AHR to RAG/ mice which lack
gen sensitized and challenged mice. There are few reports of both B- and T-lymphocytes [22]. It has since been estab-
comparisons of the various protocols in terms of their abil- lished that other T-cell subsets including -T-cells, iNKT
ity to induce AHR, but those available indicate that both cells, and regulatory T-cells may have roles in enhancing or
systemic sensitization and pulmonary challenge are required attenuating allergic airways disease in these mouse models
to induce AHR [9]. For example, multiple airway chal- [2326].
lenges without systemic sensitization can result in pulmo- A major focus of research using these models over the
nary eosinophilia, but in vivo AHR is not observed under last decade has been to establish how T-lymphocytes con-
these conditions [10]. The route of airway challenge (nasal tribute to allergic airway responses. Early on, it was estab-
or intratracheal versus aerosol) may also be a factor [11]. lished that the ability of these cells to generate cytokines
Mouse strain also has an important impact on allergen- was likely to be important. Initial work focused on IL-4,
induced AHR. AHR is relatively easy to induce in Balb/c IL-5, and IL-13 [19, 20, 22, 2731]. More recently, other
and A/J mice, but more dicult to induce in other strains, cytokines, including IL-17, have received increasing atten-
including C57BL/6 mice even though airway inammation tion [3234].
is robust in this strain [9, 1214]. The relative resistance of Role of IgE and mast cells in allergen-induced AHR:
C57BL/6 mice to allergen-induced AHR is unfortunate, Mast cells express receptors (Fc RI) on their surface that
since many of the knockout mice that could be used to bind the Fc portion of IgE with high anity. Crosslinking
study the mechanistic basis for allergen-induced AHR are Fc RI receptors upon binding of allergen to IgE results in
originally developed on this background. the secretion of a panel of mediators including histamine,
Recently, investigators have begun using repeated aller- eicosanoids, and cytokines, many of which have the capac-
gen challenges over several weeks to months to model the ity to cause bronchoconstriction and to elicit AHR, though
airway remodeling that characterizes human asthma [15]. In it is important to note that IgE independent activation of
general, such challenges often result in tolerance, although mast cells can occur in response to complement proteins,
in the A/J strain, eosinophilia and AHR are preserved over neuropeptides, and other moieties. In humans, activation
several months, and these mice develop subepithelial bro- of mast cells by IgE is important for both early and late
sis and airway smooth muscle hypertrophy [12]. However, responses to allergen inhalation: treatment with the human-
modications to the protocols may improve the utility of ized anti-IgE antibody, omalizumab, markedly reduces both
mouse models for studies of airway remodeling. A recent the rapid and delayed declines in FEV1 that occur following
report by Yu et al. [16] indicates that elimination of adjuvant inhalation of allergen [35]. An important drawback of using
during the sensitization phase results in preserved AHR, mice is that such airway obstruction is not easily observed
eosinophilia, and subepithelial brosis even after 9 weeks of [36]. Small increases in pulmonary resistance (RL) (less than
repeated weekly intranasal challenges in mice on a C57BL/6 50% increase) can be observed following systemic admin-
background. Others have observed subepithelial brosis and istration of activating anti-IgE antibodies [37], but RL
increases in airway smooth muscle mass after chronic chal- changes little after airway challenge with allergen [36]. This
lenge over several months with very low concentrations of is in marked contrast to many other species which develop
OVA delivered intranasally, even in C57BL/6 mice [17]. marked increases in RL after inhalation of allergen [3840].

100
Asthma and COPD: Animal Models 8
Mast cells and IgE also appear to play a role in the cytokines involved. Renements in these models involv-
airway inammation that occurs after allergen challenge in ing chronic challenges may ultimately allows us to use such
asthmatics [41], but the ability of mouse models to repro- models to study the airway remodeling that characterizes
duce this phenomenon has not been consistent. Kung et al. asthma, but are currently in their infancy. The protocol used
[42] reported that aerosol OVA challenge of systemically to sensitize and challenge the mice, and the choice of mouse
sensitized mast cell decient mice resulted in fewer eosi- strain are key issues and can inuence outcome.
nophils in BAL uid and lung tissue compared to congenic
controls, whereas others [10, 4345] have failed to observe
any eect of mast cell deciency or IgE deciency on the Modeling obesity and asthma
recruitment of eosinophils. At least part of this discrepancy
is likely related to the precise protocol used to sensitize and Obesity is a risk factor for asthma. Both in adults and
challenge the mice. Kobayashi et al. used two distinct pro- children, the prevalence and incidence of asthma increase
tocols to sensitize and challenge mast cell decient mice with body mass index (BMI) (see recent reviews [5558]).
and found reduced eosinophils compared to strain matched Obesity also appears to worsen asthma control and may
controls when relatively mild protocols for airway challenge increase asthma severity. In addition, both surgical and
that resulted in relatively few eosinophils were employed, diet-induced weight loss improve many asthma out-
but no dierence between mast cell decient and control comes. The ecacy of many standard asthma medications
mice when more frequent and robust airway challenges that is altered in the obese [58, 59], suggesting that additional
produced marked increases in eosinophils were used [43]. therapeutic strategies may be necessary in this population.
Role of eosinophils in allergen-induced AHR: Eosinophils Development of these strategies will require an understand-
contain cationic proteins such as major basic protein (MBP) ing of the mechanistic underpinnings of the relationship
that have the capacity to induce AHR [46] and experiments between obesity and asthma. To that end, mice have been
in mice in the late 1990s provided strong evidence that eosi- used to model the relationship between obesity and asthma.
nophils may be responsible for the AHR associated with These studies have established that obese mice exhibit a
allergic asthma. For example, in mice, transgenic overexpes- pulmonary phenotype that includes both innate AHR,
sion of IL-5, a dierentiation, chemoattractant, and survival as well as increased responses to ozone (O3) and allergen
factor for eosinophils, led to accumulations of eosinophils [6065], and suggest a role for adipokines in the obesity
and AHR even in the absence of allergen challenge [47]. asthma relationship [66, 67].
Following OVA sensitization and challenge, both accumula- Several types of obese mice have been used in these
tion of eosinophils in the airways and AHR were prevented studies (see Ref. [68] for details). Ob/ob mice are geneti-
in IL-5 decient compared to wild-type mice and recon- cally decient in leptin, a satiety hormone synthesized by
stitution of IL-5 in these knockout mice restored pulmo- adipocytes and released into blood in proportion to adipose
nary eosinophilia and AHR [48, 49]. Similar results were tissue mass. In the absence of leptin, ob/ob mice eat exces-
obtained using anti-IL-5 antibodies [50]. The observation sively, have a low resting metabolic rate, and by 8 weeks
of a good correlation between airway eosinophils and AHR of age weigh at least twice as much as wild-type controls
across multiple strains of mice, all sensitized and challenged [69]. The increased body weight is entirely the result of an
in the same way, also argued for a relationship between these increase in fat mass. Db/db mice are genetically decient in
factors [13]. Data such as those cited above were strong the long form of the leptin receptor, which is required for
enough to initiate clinical trials for anti-IL-5 in human leptins eect on satiety and metabolism [69]. Thus, db/db
asthma. However, the results of such trials have been dis- mice are similar to ob/ob mice in many respects: they over-
appointing. For example, a recent fairly large study showed eat, are hypothermic and inactive, and massively obese.
that while anti-IL-5 antibody treatment results in marked However, short forms of the leptin receptor with truncated
suppression of both blood and sputum eosinophils, it does or absent cytoplasmic domains are expressed in these mice,
not impact pulmonary function, -agonist use, symptom and are capable of some types of signaling. Hence, there can
or quality of life scores in patients with persistent asthma be subtle dierences between ob/ob and db/db mice, includ-
symptoms despite inhaled corticosteroid use [51], although ing dierences in their pulmonary phenotype [60]. Cpe fat
it has been argued that the study population (one of dicult mice are genetically decient in carboxypeptidase E (Cpe),
to control asthma) could have biased the study [52]. Did our an enzyme involved in processing of neuropeptides involved
mouse models lead us astray? There are certainly data from in eating behaviors. Obesity develops more slowly in these
mouse models arguing against a role for eosinophils in the mice than in ob/ob or db/db mice, but can be quite marked
AHR associated with allergen sensitization and challenge [69]. Dietary obesity can also be induced by feeding wean-
[19, 53, 54]. Mouse strain and the strength of the allergen ling C57BL/6 mice a diet in which 45% or 60% of calories
challenge appear to impact whether a role for eosinophils are derived from fat (predominantly in the form of lard).
are observed or not: experiments performed in Balb/c mice Diet-induced obesity (DIO) develops slowly and is much
in which milder challenges are used indicate little role for less marked than in the genetic obesities. All of these obese
eosinophils in OVA-induced AHR [5]. mice are hyperglycemic, hyperinsulinemic, and hyperlipi-
Summary: Mice are not useful for modeling the early demic to some extent [68, 69].
or late responses to allergen, but models in which mice are Innate AHR: Airway responsiveness to intrave-
sensitized and then challenged with allergen have been use- nous methacholine is increased in ob/ob, db/db, and Cpe fat
ful in establishing a role for T-lymphocytes in asthma and mice, and in mice with DIO [6065], indicating that it is
are currently being used to investigate the T-cell subsets and a common feature of murine obesity. Consistent with the

101
Asthma and COPD: Basic Mechanisms and Clinical Management

non-specic nature of human asthma, AHR is observed Responses to allergen: Some, but not all, aspects of
following both methacholine and serotonin challenges [60]. the response to allergen are augmented in obese mice. For
Both the magnitude and the duration of obesity appear to example, following OVA sensitization and challenge, splen-
play some role in the development of AHR in obese mice. ocyte proliferation, IL-2 production, and mast cell numbers
For example, AHR is more marked in ob/ob and db/db mice are increased in mice with DIO compared to lean controls
than in Cpe fat mice or mice with DIO. Mice do not exhibit [78]. Increased OVA-induced AHR is also observed in
AHR when they are raised on high-fat diets for approxi- obese mice [63]. However, this increase in airway respon-
mately 16 weeks, but AHR is observed after 30 weeks on siveness occurs in the absence of any dierences in Th2
the diet, even though body weight averages about 40% more cytokines and in the face of decreases in BAL eosinophils
than low-fat fed controls at both time points [61]. compared to lean controls, suggesting that other factors
The mechanistic basis for the AHR observed in obese must contribute. Interestingly, OVA-induced increases in
mice is not known. However, the mice do not have any overt serum IgE are also greater in ob/ob and db/db mice than
cellular inammation in their lungs [60, 63]. All measure- in lean controls. As described above, IgE and mast cells
ments were made in open-chested mice, mechanically venti- do not appear to contribute prominently in most studies
lated at a xed positive end-expiratory pressure (PEEP) and of allergen-induced airways disease in mice. However, the
a xed tidal volume, so changes in absolute or tidal volume expression of 5-lipoxygenase activating protein is substan-
likely do not play a role. In ob/ob and db/db mice, there are tially increased in the adipose tissue of ob/ob mice [79]. This
eects on lung development: despite their massive obesity, could lead to greater leukotriene synthesis and subsequent
these mice have small lungs [60, 65]. However, lung size is release from activated mast cells and thus enhance airway
not aected in Cpe fat mice and mice with DIO, but these responsiveness. In this context, Peters-Golden et al. recently
mice still exhibit AHR [61, 62]. Instead, it is likely that reported a more benecial eect of the leukotriene antago-
some aspect of the chronic low-grade systemic inamma- nist montelukast in obese versus lean asthmatics [80].
tion that characterizes the obese state [70] contributes to the Adipokines: Several hypotheses have been proposed
AHR observed in obese mice. For example, preliminary data to explain the association between obesity and asthma
in both db/db and Cpe fat mice indicate that treatment with (Fig. 8.1). For example, obesity results in changes in a
anti-TNF- antibodies reduces airway responsiveness [71]. variety of adipose tissue derived factors (adipokines) that
Responses to O3: Exposure to O3, a common air pollut- may contribute to the relationship between obesity and
ant, is a trigger for asthma. Hospital admissions for asthma asthma. Serum leptin is increased in obesity and two cross-
are higher on days of high ambient O3 concentrations [72] sectional studies indicate that leptin is also increased in
and in children, O3 increases asthmatic symptoms even at asthmatics [81, 82]. Numerous reports indicate that lep-
concentrations below the US Environmental Protection tin is pro-inammatory (see recent review [83]), and these
Agency standard [73]. O3 causes airway inammation, as inammatory eects could exacerbate asthma in the obese.
well as AHR, both of which may contribute to the ability Leptin treatment has been shown to augment allergen-
of O3 to exacerbate asthma. induced AHR in lean mice, without aecting eosinophil
Obesity impacts the eects of O3 in the lung. Both the inux or Th2 cytokine expression [66]. Indeed, rather than
changes in pulmonary function and the AHR induced by O3 modifying adaptive immunity, leptin could be acting on the
exposure are increased in obese versus lean human subjects innate immune system: exogenous administration of lep-
[74, 75]. Similar results are observed in obese mice regard- tin to lean mice increases their subsequent inammatory
less of the nature of their obesity. Acute exposure to O3 response to acute O3 exposure [65], a response character-
(2 ppm for 3 h) increases RL in obese but not lean mice and ized by release of acute phase cytokines and chemokines,
induces greater AHR in obese versus lean mice [60, 62, 65]. and dependent to some extent on toll-like receptor acti-
Compared to lean controls, O3-induced injury and inam- vation [84]. However, there must be factors in addition to
mation are also greater in ob/ob mice, db/db mice, Cpe fat
mice, and mice with DIO [6062, 65]. However, the factors
that contribute to the innate AHR of obese mice appear to
be dierent from those that contribute to their increased Mechanisms proposed to explain
response to acute O3: increased O3-induced inammation the relationship between obesity and asthma
is observed as early as 7 weeks of age in Cpe fat mice [76],
whereas AHR is not observed until they are 10 weeks old. Common etiologies Effects of obesity
At least part of the increased response to O3 observed In utero conditions on lung mechanics
in obese mice appears to derive from dierences in IL-6 Genetics FRC
Tidal volume
signaling. Following acute O3 exposure, obese mice have
increased IL-6 release into BAL uid compared to lean Co-morbidities Adipokines
mice [60, 62, 65]. Treatment with anti-IL-6 antibodies Gastroesophageal reflux Cytokines
ablates the accelerated neutrophil inux that is observed fol- Sleep disorder breathing Chemokines
lowing acute O3 exposure in ob/ob mice and also attenuates Type-II diabetes Energy regulating hormones
the enhanced O3-induced epithelial injury that is observed Hypertension Acute phase reactants
Other factors
in these mice [77]. Pulmonary expression of signal trans-
ducer and activator of transcription-1 (STAT-1) is reduced FIG. 8.1 Potential mechanisms whereby obesity may be associated
in ob/ob mice [77] and may modify pulmonary responses to with asthma. Reproduced from Ref. [68] with permission of the American
IL-6 in these mice. Physiological Society.

102
Asthma and COPD: Animal Models 8
leptin that contribute to the augmented O3 responses of fact that elastin fragments themselves [101] are chemok-
obese mice, since such responses are observed not only in ines, and that the events following PPE instillation are very
Cpe fat and DIO mice [61, 62] that have marked increases in similar to the inammatory cell cascade that one observes
serum leptin, but also in ob/ob and db/db mice [60, 65], that in COPD following cigarette smoke exposure. That is, ini-
lack either leptin or the leptin receptor. tially PPE leads to acute airspace enlargement with elastin
In contrast to other adipokines, adiponectin, an insulin- destruction and release of fragments of elastin and other
sensitizing hormone, declines in obesity [85, 86]. In contrast matrix proteins. This results in subsequent neutrophilia fol-
to leptin, adiponectin has important anti-inammatory lowed within days by a predominant macrophage and T-cell
eects in obesity [86]. In lean Balb/c mice, exogenous admin- inux. These activated inammatory cells release endog-
istration of adiponectin results in an almost complete sup- enous elastases causing progressive airspace enlargement.
pression of OVA-induced AHR, airway inammation, and Environmental factors: Cigarette smoke is clearly the
Th2 cytokine expression in the lung [67]. Adiponectin has major etiologic factor for COPD. However, a variety of other
been shown to inhibit macrophage production of lymphocyte environmental agents have been applied to determine their
chemotactic factors [87]. An adiponectin-induced reduc- capacity to induce COPD. Nitrogen dioxide and ozone cause
tion in lymphocyte inux into the lungs would be expected mild lung injury suggesting that they may be modifying envi-
to reduce pulmonary concentrations of Th2 cytokines and ronmental factors but unlikely primary environmental factors
could thus be responsible for attenuating eosinophilia and leading to COPD [90]. Cadmium chloride [102], a constitu-
AHR following OVA challenge. Three adiponectin receptors ent of cigarette smoke, primarily causes interstitial brosis
have been cloned: adipoR1, adipoR2, and T-cadherin [88, tethering open adjoining airspaces simulating emphysema.
89]. Lung tissue expresses all three adiponectin receptors. While this mechanism diers from airspace enlargement
The expression of all three receptors declines in the lungs fol- secondary to matrix destruction that characterizes emphy-
lowing allergen sensitization and challenge in mice [67], sug- sema, excess collagen deposition in the context of loss of
gesting that asthma may be a state of adiponectin resistance. elastin is a feature of human centrilobular emphysema.
Coupled with obesity-related declines in adiponectin [85, Cigarette smoke [4, 94, 95]: The great strength of ciga-
86] and additional declines in serum adiponectin that occur rette smoke-induced models of COPD is that we know
with allergen challenge [67], the data suggest that the obese that this is the causative agent for COPD. Hence, path-
asthmatic is likely to have defects in this important immuno- ways leading to phenotypic changes of COPD mirror those
modulatory pathway that augment the eects of allergen of human COPD, limited only by dierences in smoke
challenge. exposure as well as biological dierences between mice and
humans. Over the years many species of mammals have
been exposed to cigarette smoke using a variety of smok-
ing chambers. Larger animals are limited by the long (years)
MOUSE MODELS OF COPD duration of exposure required for development of COPD.
Of small animals tested, the guinea pig is the most suscep-
tible species and rat the least. Several inbred mouse strains
Modeling COPD are also susceptible to cigarette smoke-induced COPD, and
hence they have dominated the literature due to our ability
Animal models were critical to the development of the to manipulate gene expression as well as other advantages
elastase:anti-elastase hypothesis generated 45 years ago. This discussed above.
hypothesis remains the cornerstone of our understanding of Following exposure to cigarette smoke, mice develop
COPD pathogenesis today. The major nding at that time changes similar to humans including acute inammation
was that instillation of the proteinase papain into experi- with neutrophils followed by subacute increases in macro-
mental animals caused airspace enlargement, the charac- phages, and CD8  CD4 T-cells [103]. Proteinases are
teristic feature of emphysema [1]. Since then animals have released and apoptosis of structural cells is observed. These
been exposed to a variety of molecular, chemical, and envi- processes ultimately lead to airspace enlargement that is
ronmental agents that lead to airspace enlargement [90]. In easily detectable in most strains within 6 months. With
particular elastases [9193], cigarette smoke [94, 95], and respect to the airway, mice lose cilia upon cigarette smoke
more recently inducers of apoptosis have been most inform- exposure, develop small airway brosis, and also develop
ative [96, 97]. Mouse genetic mutants have also been criti- goblet cell hypertophy [4, 104].
cal in furthering our understanding of the pathogenesis of Apoptosis: Recently investigators have found that
COPD [4, 95]. exposure to agents that initiate either endothelial cell death
Elastases: Ever since the initial ndings with papain, a (via VEGFRII inhibition) [96] or epithelial cell death
variety of proteinases have been instilled into experimental (via caspase 3 nodularin, ceramide delivery, and VEGF
animals. Of note, only those with elastolytic activity develop inhibition) [97, 105, 106] lead to non-inammatory air-
emphysema, collagenases do not [91]. Of most utility space enlargement. Clearly, to lose an acinar unit, one
has been porcine pancreatic elastase (PPE) [91, 98, 99], a must destroy both extracellular matrix (ECM) and struc-
potent elastase that quickly generates airspace enlargement. tural cells. Traditionally, we believed that inammatory
This model has also been useful to test agents that have the cell proteinases destroy ECM and cells unable to attach to
capacity to restore lung structure such as retinoic acid [100]. the ECM oat away and die. The apoptotic models sug-
A recent surprise has been the usefulness of PPE to model gest death of structural cells may be an initiating event,
events upstream from elastolysis. This is likely due to the with subsequent release of matrix degrading proteinases.

103
Asthma and COPD: Basic Mechanisms and Clinical Management

Whether this occurs in human COPD as a primary event is cells and mediators are involved. Investigators are now
uncertain, but does raise interesting testable possibilities. focused on teasing out mechanisms that lead to this com-
Genetic models: Natural genetic mutants, transgenic mice, plex network and the interactions between these cells and
and gene-targeted mice, may develop spontaneous airspace their mediators that leads to COPD.
enlargement of developmental origin. They may also develop Upon acute exposure to cigarette smoke one observes
progressive airspace enlargement acquired spontaneously over activation of macrophages and structural cells that leads
time that more closely reects the destruction of mature lung to a mild, acute, transient accumulation of neutrophils in
tissue characteristic of emphysema [4, 99]. Overexpression or the lung. Over days to weeks one also observes increased
underexpression of a protein during development that leads number of T-cells, particularly CD8 T-cells, and mac-
to failed alveogenesis and enlarged airspaces is very informa- rophages [107]. Neutrophils accumulate with each acute
tive regarding pathways required for normal lung develop- exposure, but due to the short-half life of the neutrophil do
ment and hence repair in emphysema. However, this is very not accumulate to high levels. The longer-lived macrophages
dierent from destruction and enlargement of normal mature and T-cells progressively accumulate with chronic smoke
alveoli that denes pulmonary emphysema. exposure. In humans, one observes B-cell accumulation in
If overexpression of a protein in transgenic mice leads bronchialalveolar lymphoid tissue (BALT) late in the dis-
to airspace enlargement in the adult, then if the protein is ease. While this could be secondary to bacterial coloniza-
overexpressed in the endogenous process it is likely to play tion in humans, it has also been observed in mice exposed
a role. For example, instillation of PPE mimics emphysema to cigarette smoke in the absence of infection [108].
quite well, but of course PPE does not travel from the gut An undoubtedly simplistic but unied pathway, sup-
to the lung in true emphysema. ported by data from cigarette smoke-exposed mice, can
Of most utility in dissecting the pathogenesis of account for much of the inammation observed in response
COPD are developmentally normal gene-targeted mice to cigarette smoke. Cigarette smoke, via its oxidant prop-
applied to cigarette smoke. Protection of a knockout with erties, can activate macrophages leading to TNF- pro-
smoking suggests that the protein deleted is involved in a duction with latent TNF- translocating to the surface
pathway that promotes COPD, while worsening COPD whereupon MMP-12 sheds active TNF- leading to
suggests a protective factor was deleted. There are many neutrophil recruitment and activation [109].
proteins that have been identied using these techniques as Release of MMP-12 from macrophages and colla-
recently reviewed [99]. Knowledge gained from these stud- genases MMP-8 and MMP-13 (MMP-1 not expressed in
ies will be synthesized below. mice) from macrophages and likely epithelial cells leads to
Limitations: The mouse lung structure is not identical generation of elastin and collagen fragments respectively.
to humans. Mice do not inhale cigarettes as humans would Elastin fragments serve as chemokines for macrophages
and these obligate nasal breathers bring the smoke through [101] and collagen fragments promote neutrophil recruit-
an extensive olfactory epithelium into the airway where ment [110]. Indeed, in humans CXC and CC chemokines
there are few submucosal glands, much less airway branch- may play a signicant role in inammatory cell migration,
ing, and no respiratory bronchioles the initial site of cen- particularly when colonized with bacteria. However, in mice
triacinar emphysema. Hence, mice do not develop small under sterile conditions, elastin fragments appear to be crit-
airway disease that is so important in human COPD. ical to the low-level macrophage accumulation one observes
Nevertheless, the opportunity exists to infect mouse airways in response to cigarette smoke.
with relevant human pathogens to learn more about airway T-lymphocytes, particularly CD8 T-cells, are
changes and exacerbations of COPD. increased in lungs of patients with COPD [111].
Mice require months of cigarette smoke exposure to Overexpression of the T-cell product IFN in transgenic
develop mild emphysema. These are more likely to reect mice, results in apoptosis, inammation, and emphysema
Global Initiative for Chronic Obstructive Lung Disease [112]. Moreover, IFN and IFN-IP-10 (interferon-
(GOLD) stage I and II not the severe stages of COPD (III gamma-inducible protein-10) have been shown to be
and IV). Moreover, there is a variety of smoking chambers increased in CD8 T-cells from patients with emphysema,
now available that dier with respect to the mode, rate, and and IP-10 was also shown to induce the production of
amount of smoke delivered. Particulate amounts, carboxy- MMP-12 in human alveolar macrophages [113]. In addi-
hemoglobin levels, and other surrogates of exposure are tion to this potentially indirect inuence of CD8 T-cells
often measured to assess how well these mimic human on emphysema, they may also directly cause cytotoxicity
exposure. The most important features are the resultant contributing to emphysema. The importance of the CD8
phenotypic changes in the exposed animals and their rela- T-cell in the pathogenesis of emphysema, was recently con-
tionship to humans. One note of caution is that excessive rmed by subjecting wild-type (C57BL/6 J), CD8 T-cell
acute exposure to smoke leads to acute lung injury with pro- decient (CD8/) mice, and CD4 T-cell decient (CD4/)
nounced neutrophilia, which is not likely to reect COPD. mice to a model of cigarette smoke-induced emphysema
[107]. In the absence of CD8 T-cells, but not CD4
T-cells, there was a marked inhibition in inammation and
Lessons from mouse models of COPD emphysema. Integrating these results into the network,
one can conclude that CD8 T-cells via production of IP-
Inammatory cell network in COPD: Animal models have 10, signal through macrophage CXCR3 to activate the mac-
taught us that emphysema is not caused by a single cell type rophage leading to proteinase and cytokine production. The
or proteinase. Rather, multiple inammatory and immune macrophage then recruits neutrophils, and their proteinases

104
Asthma and COPD: Animal Models 8
then degrade ECM, particularly elastin and collagen, con- Lung-specic transgenic mice expressing either the Th2
tinuing the inammatory cascade. Hence, CD8 T-cells cytokine IL-13 (Dutch mice) [121] or the Th1 cytokine
may be the master regulator of inammation in COPD. IFN- (British mice) [112] both develop proteinase-
Of note, these results are entirely consistent with data from dependent emphysema. IFN- overexpressors develop a
human COPD. cysteine proteinase/apoptosis mediated form of emphysema,
Defects in adaptive immunity are also likely to play an while IL-13 overexpression induces inammation with
important role with respect to colonization of microorganisms MMP-12- and MMP-9-dependent airspace enlargement.
in the airway and exacerbations. Prolonged cigarette smoke IL-13 transgenic mice also develop small airway remodeling
exposure (1 month) in mice results in a decrease in lung den- that is believed to be due to MMP-9-dependent activation
dritic cell (DC) number, but DC migration to regional tho- of TGF- with airway brosis [122]. The role of TGF- in
racic lymph nodes remains intact. Once in the lymph nodes, emphysema was also highlighted with avb6/ mice, that
however, cigarette smoking suppresses maturation of DCs as are unable to activate TGF- in the airspace, develop mac-
demonstrated by the reduced expression of co-stimulatory rophage inammation and MMP-12-dependent emphy-
molecules. Moreover, these cigarette smoke exposed DC cells sema [123]. TGF- regulation is complex as total absence
have impaired capacity to activate CD4 T-cells with less of TGF- releases the brake on inammation and destruc-
IL-2 production and diminished T-cell proliferation [114]. tion in the airspace while too much TGF- leads to brosis
Impaired CD4 T-cell activation would predispose patients in the airways.
to colonization with infectious microorganisms. Other gene-targeted mice that develop emphysema
As discussed, B-cells and BALT are present in include surfactant protein D/ (SP-D/) mice, which
COPD lung tissue, however, their role in the disease process exhibit macrophage activation, MMP production, and con-
remains to be determined. Of note, recent animal [115] and sequent emphysema [124]. TIMP-3 deciency leads to a
human [116] studies have implicated autoimmune processes combination of developmental airspace enlargement com-
in the pathogenesis of COPD. In fact, elastin fragments bined with progressive destructive emphysema in adults
themselves were shown to be an important autoimmunue [125], supporting the role of MMPs in COPD. There is also
target in COPD in human studies [116]. Other cell types evidence from animal models that neutrophil elastase (NE),
including eosinophils, mast cells, and natural killer (NK) a serine proteinase long thought to cause COPD, is also
cells are also likely to be involved in this inammatory cell involved in experimental emphysema. NE/ mice develop
network, but to date, they have not been carefully addressed. only 40% as much airspace enlargement as wild-type mice
Role of oxidative stress in COPD: Cigarette smoke, exposed to long-term cigarette smoke [126]. These stud-
loaded with 1017 oxidant molecules per pu leads to ies have uncovered several interactions between NE and
increased oxidative stress in smokers and in patients with MMPs. MMPs degrade 1-AT and NE degrades TIMPs,
COPD. Oxidative stress, in part through inactivation of each potentiating the others proteinase activity. Moreover,
histone deacetylases, exposes DNA sequences and activates NE mediates monocyte migration and as discussed, acute
transcription factors for inammatory genes, such as nuclear neutrophil inammation secondary to smoking is related to
factor-B (NF-B) and activator protein (AP)-1 [117]. This MMP-12-dependent TNF-shedding [109].
nding, initially in humans, has been conrmed in rodents Role of apoptosis in COPD: As discussed above, induc-
exposed to cigarette smoke [118]. Oxidants also have a sig- tion of structural cell apoptosis leads to airspace enlarge-
nicant role in promoting apoptosis, and although oxidants ment. However, there are some aspects of these models that
do not directly degrade ECM proteins, they might modify do not mimic human disease. They are non-inammatory
these proteins making them more susceptible to proteo- and transient, which is likely related to their lack of matrix
lytic cleavage. Oxidative stress also can alter the structure degradation. Most importantly, however, closer pathologic
of pro-MMPs leading to autolytic cleavage and activation and physiologic examination of at least one model of epi-
[119]. Gene deletion of Nrf-2 a master transcription fac- thelial cell apoptosis demonstrates that this model is not
tor for antioxidant genes also leads to enhanced emphysema emphysema per se, but acute lung injury with collapsed alve-
in response to cigarette smoke exposure highlighting the oli tethering of open adjoining airspaces to appear enlarged
importance of oxidative stress in COPD [120]. (Mouded M and Shapiro SD, unpublished observations).
Role of proteinases in COPD: As mentioned at the Thus, like other traditional models of epithelial apoptosis,
beginning of this chapter and reviewed in depth in the bleomycin being the classic, the result is acute lung injury
Matrix Degrading Proteinase (Chapter 28), ECM and if severe, brosis. Endothelial apoptosis could have a
destruction by proteinases is the cornerstone of emphysema. dierent outcome, but it is likely that apoptosis does not
Animal models have played an important role in dening initiate emphysema. Apoptosis, however, is likely to be a
the contribution of dierent elastolytic enzymes in this critically important modier in the pathogenesis of COPD.
process. In addition to the original instillation of papain by For example, as in humans, apoptosis is observed in animal
Gross [1], in one of the rst applications of gene-targeted models following cigarette smoke exposure, likely due to
mice to lung disease, it was shown that macrophage elastase loss of basement membrane attachment / oxidant eects
(MMP-12) decient mice were protected from the develop- of cigarette smoke. The fate of the apoptotic cell is criti-
ment of emphysema [95]. As in several other models of dis- cal to disease progression. Clearance by macrophages leads
ease, MMP-12 is pro-inammatory, which in part is related to anti-inammatory TGF- production and release of
to the generation of chemotactic elastin fragments [101]. growth factors that promote repair [127]. Inecient clear-
Subsequently, several other animal models have ance leads to secondary necrosis, augmenting inammation
demonstrated the importance of proteinases in COPD. and destruction.

105
Asthma and COPD: Basic Mechanisms and Clinical Management

Role of repair in COPD: The ability of the adult lung References


to repair damaged alveoli appears limited. This is likely due
to the structural and functional dependence upon the elas- 1. Gross P, Ptzer E, Tolker M. Experimental emphysema: Its produc-
tic ber architecture combined with the diculty in repair- tion with papain in normal and silicotic rats. Arch Environ Health 11:
ing elastic bers. Whether one can temporally and spatially 5058, 1965.
bring together the multiple microbrillar components of an 2. Drazen JM, Israel E, OByrne PM. Treatment of asthma with drugs
elastic ber let alone coordinate matrix repair with endothe- modifying the leukotriene pathway. N Engl J Med 340: 197206, 1999.
lial and epithelial migration and dierentiation over an 3. Shapiro SD. Animal models of asthma: Pro: Allergic avoidance of ani-
injured matrix is unknown. mal (model[s]) is not an option. Am J Respir Crit Care Med 174: 1171
73, 2006.
With the emergence of regenerative medicine and
4. Shapiro SD. Transgenic and gene-targeted mice as models for chronic
stem cell biology, there is hope that we can one day cre- obstructive pulmonary disease. Eur Respir J 29: 37578, 2007.
ate new functional lung tissue. However, given the com- 5. Boyce JA, Austen KF. No audible wheezing: Nuggets and conundrums
plex three-dimensional nature of the lung, its regeneration from mouse asthma models. J Exp Med 201: 186973, 2005.
presents a special challenge relative to other organs. It is 6. Wenzel S, Holgate ST. The mouse trap: It still yields few answers in
currently not known whether there is a master stem cell, asthma. Am J Respir Crit Care Med 174: 117376, 2006. Discussion
separate progenitors for each cell type, nor what their repar- 117678.
ative capacity is. More importantly, given the collapse of the 7. Zosky GR, Sly PD. Animal models of asthma. Clin Exp Allergy 37:
elastic ber cable network, it is unclear whether stem cells 97388, 2007.
alone could regenerate a functional alveolar unit. 8. Lommatzsch M, Julius P, Kuepper M, Garn H, Bratke K, Irmscher
S, Luttmann W, Renz H, Braun A, Virchow JC. The course of aller-
There has been some evidence that one can repair
gen-induced leukocyte inltration in human and experimental asthma.
emphysematous lung tissue in animal models. The study J Allergy Clin Immunol 118: 9197, 2006.
by Massaro et al. [100] discussed above, showing that all- 9. Zhang Y, Lamm WJ, Albert RK, Chi EY, Henderson WR Jr., Lewis DB.
trans retinoic acid reversed PPE-mediated emphysema, has Inuence of the route of allergen administration and genetic back-
led to hope that we might be able to promote lung repair ground on the murine allergic pulmonary response. Am J Respir Crit
[100]. Use of retinoic acid did not have signicant eects in Care Med 155: 66169, 1997.
human trials, but has opened the door to mechanisms that 10. Hamelmann E, Tadeda K, Oshiba A, Gelfand EW. Role of IgE
could be reparative. in the development of allergic airway inammation and airway
There have been attempts to add growth factors, such hyperresponsiveness a murine model. Allergy. 54: 297305, 1999.
as keratinocyte growth factor (KGF) to elastase-treated 11. Shore SA. Modeling airway remodeling: The winner by a nose? Am J
Respir Crit Care Med 168: 91011, 2003.
lungs. The results demonstrate the ability to protect from
12. Shinagawa K, Kojima M. Mouse model of airway remodeling: Strain
injury, but not repair damaged tissue [128]. The advent of dierences. Am J Respir Crit Care Med 168: 95967, 2003.
lineage tagged and lineage ablated genetically engineered 13. Brewer JP, Kisselgof AB, Martin TR. Genetic variability in pulmonary
mice will be helpful to dene progenitor cells and their physiological, cellular, and antibody responses to antigen in mice. Am J
reparative capacity in the future. Respir Crit Care Med 160: 115056, 1999.
14. Ewart SL, Kuperman D, Schadt E, Tankersley C, Grupe A,
Shubitowski DM, Peltz G, Wills-Karp M. Quantitative trait loci con-
trolling allergen-induced airway hyperresponsiveness in inbred mice.
Am J Respir Cell Mol Biol 23: 53745, 2000.
SUMMARY 15. Lloyd CM. Building better mouse models of asthma. Curr Allergy
Asthma Rep 7: 23136, 2007.
16. Yu M, Tsai M, Tam SY, Jones C, Zehnder J, Galli SJ. Mast cells can
It is important to keep in mind that there are important promote the development of multiple features of chronic asthma in
structural dierences in the lungs of mice and humans and mice. J Clin Invest 116: 163341, 2006.
to interpret animal data with caution. In some instances, 17. Lim DH, Cho JY, Miller M, McElwain K, McElwain S, Broide DH.
murine models of allergic asthma have not recapitulated Reduced peribronchial brosis in allergen-challenged MMP-9-decient
the human ndings, and have led to some costly failures mice. Am J Physiol Lung Cell Mol Physiol 291: L265271, 2006.
in drug development. Nevertheless, animal models have 18. Garssen J, Nijkamp FP, Van Der Vliet H, Van Loveren H. T-cell-
mediated induction of airway hyperreactivity in mice. Am Rev Respir
been extremely useful in the evolution of current concepts
Dis 144: 93138, 1991.
regarding the etiology of asthma and COPD and geneti- 19. Corry DB, Folkesson HG, Warnock ML, Erle DJ, Matthay MA,
cally engineered mice continue to drive the generation and Wiener-Kronish JP, Locksley RM. Interleukin 4, but not interleukin
testing of new hypotheses. 5 or eosinophils, is required in a murine model of acute airway hyper-
reactivity. J Exp Med 183: 10917, 1996.
20. Brusselle GG, Kips JC, Tavernier JH, van der Heyden JG, Cuvelier
CA, Pauwels RA, Bluethmann H. Attenuation of allergic airway
inammation in IL-4 decient mice. Clin Exp Allergy 24: 7380, 1994.
ACKNOWLEDGEMENTS 21. Gavett SH, Chen X, Finkelman F, Wills-Karp M. Depletion of murine
CD4 T lymphocytes prevents antigen-induced airway hyperreactivity
and pulmonary eosinophilia. Am J Respir Cell Mol Biol 10: 58793, 1994.
The authors work is supported by National Institute of 22. Corry DB, Grunig G, Hadeiba H, Kurup VP, Warnock ML, Sheppard D,
Environmental Health Sciences Grants ES-013307 and Rennick DM, Locksley RM. Requirements for allergen-induced air-
ES-00002, and National Heart, Lung, and Blood Institute way hyperreactivity in T and B cell-decient mice. Mol Med 4: 34455,
Grants HL-084044 and HL-082541. 1998.

106
Asthma and COPD: Animal Models 8
23. Zuany-Amorim C, Rue C, Haile S, Vargaftig BB, Pereira P, 42. Kung TT, Stelts D, Zurcher JA, Jones H, Umland SP, Kreutner W,
Pretolani M. Requirement for gammadelta T cells in allergic airway Egan RW, Chapman RW. Mast cells modulate allergic pulmonary
inammation. Science 280: 126567, 1998. eosinophilia in mice. Am J Respir Cell Mol Biol 12: 4049, 1995.
24. Randolph DA, Stephens R, Carruthers CJ, Chaplin DD. Cooperation 43. Kobayashi T, Miura T, Haba T, Sato M, Serizawa I, Nagai H, Ishizaka K.
between Th1 and Th2 cells in a murine model of eosinophilic airway An essential role of mast cells in the development of airway hyperre-
inammation. J Clin Invest 104: 102129, 1999. sponsiveness in a murine asthma model. J Immunol 164: 385561, 2000.
25. Meyer EH, DeKruy RH, Umetsu DT. T cells and NKT cells in the 44. MacLean JA, Sauty A, Luster AD, Drazen JM, De Sanctis GT.
pathogenesis of asthma. Annu Rev Med 59: 28192, 2008. Antigen-induced airway hyperresponsiveness, pulmonary eosinophilia,
26. Strickland DH, Stumbles PA, Zosky GR, Subrata LS, Thomas JA, and chemokine expression in B cell-decient mice. Am J Respir Cell
Turner DJ, Sly PD, Holt PG. Reversal of airway hyperresponsiveness Mol Biol 20: 37987, 1999.
by induction of airway mucosal CD4 CD25 regulatory T cells. J Exp 45. Takeda K, Hamelmann E, Joetham A, Shultz LD, Larsen GL, Irvin CG,
Med 203: 264960, 2006. Gelfand EW. Development of eosinophilic airway inammation and
27. Lukacs NW, Strieter RM, Chensue SW, Kunkel SL. Interleukin-4- airway hyperresponsiveness in mast cell-decient mice. J Exp Med 186:
dependent pulmonary eosinophil inltration in a murine model of 44954, 1997.
asthma. Am J Respir Cell Mol Biol 10: 52632, 1994. 46. Gleich GJ. The eosinophil and bronchial asthma: Current understanding.
28. Kips JC, Brusselle GG, Joos GF, Peleman RA, Devos RR, Tavernier JH, J Allergy Clin Immunol 85: 42236, 1990.
Pauwels RA. Importance of interleukin-4 and interleukin-12 in allergen- 47. Lee JJ, McGarry MP, Farmer SC, Denzler KL, Larson KA,
induced airway changes in mice. Int Arch Allergy Immunol 107: 11518, Carrigan PE, Brenneise IE, Horton MA, Haczku A, Gelfand EW,
1995. Leikauf GD, Lee NA. Interleukin-5 expression in the lung epithe-
29. Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, lium of transgenic mice leads to pulmonary changes pathognomonic of
Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, asthma. J Exp Med 185: 214356, 1997.
Corry DB. Requirement for IL-13 independently of IL-4 in experi- 48. Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin
mental asthma [see comments]. Science 282: 226163, 1998. 5 deciency abolishes eosinophilia, airways hyperreactivity, and lung
30. Hamelmann E, Wahn U, Gelfand EW. Role of the Th2 cytokines in damage in a mouse asthma model [see comments]. J Exp Med 183:
the development of allergen-induced airway inammation and hyper- 195201, 1996.
responsiveness. Int Arch Allergy Immunol 118: 9094, 1999. 49. Hamelmann E, Takeda K, Haczku A, Cieslewicz G, Shultz L, Hamid Q,
31. Wills-Karp M, Luyimbazi J, Xu X, Schoeld B, Neben TY, Karp CL, Xing Z, Gauldie J, Gelfand EW. Interleukin (IL)-5 but not immu-
Donaldson DD. Interleukin-13: Central mediator of allergic asthma noglobulin E reconstitutes airway inammation and airway hyper-
[see comments]. Science 282: 225861, 1998. responsiveness in IL-4-decient mice. Am J Respir Cell Mol Biol 23:
32. He R, Oyoshi MK, Jin H, Geha RS. Epicutaneous antigen exposure 32734, 2000.
induces a Th17 response that drives airway inammation after inhala- 50. Hogan SP, Mould A, Kikutani H, Ramsay AJ, Foster PS. Aeroallergen-
tion challenge. Proc Natl Acad Sci USA 104: 1581722, 2007. induced eosinophilic inammation, lung damage, and airways hyperre-
33. Karwot R, Maxeiner JH, Schmitt S, Scholtes P, Hausding M, Lehr HA, activity in mice can occur independently of IL-4 and allergen-specic
Glimcher LH, Finotto S. Protective role of nuclear factor of activated immunoglobulins. J Clin Invest 99: 132939, 1997.
T cells 2 in CD8() long-lived memory T cells in an allergy model. 51. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M,
J Allergy Clin Immunol 121(4): 99299, 2008. Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT, Barnes NC.
34. Pichavant M, Goya S, Meyer EH, Johnston RA, Kim HY, A study to evaluate safety and ecacy of mepolizumab in patients with
Matangkasombut P, Zhu M, Iwakura Y, Savage PB, DeKruy RH, moderate persistent asthma. Am J Respir Crit Care Med 176: 106271,
Shore SA, Umetsu DT. Ozone exposure in a mouse model induces air- 2007.
way hyperreactivity that requires the presence of natural killer T cells 52. OByrne PM. The demise of anti IL-5 for asthma, or not. Am J Respir
and IL-17. J Exp Med 205: 38593, 2008. Crit Care Med 176: 105960, 2007.
35. Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, 53. Hessel EM, Van Oosterhout AJ, Van Ark I, Van Esch B, Hofman G,
Fick RB Jr., Boushey HA. The eect of an anti-IgE monoclonal anti- Van Loveren H, Savelkoul HF, Nijkamp FP. Development of airway
body on the early- and late-phase responses to allergen inhalation in hyperresponsiveness is dependent on interferon-gamma and independ-
asthmatic subjects. Am J Respir Crit Care Med 155: 182834, 1997. ent of eosinophil inltration. Am J Respir Cell Mol Biol 16: 32534,
36. Zosky GR, Larcombe AN, White OJ, Burchell JT, Janosi TZ, Hantos Z, 1997.
Holt PG, Sly PD, Turner DJ. Ovalbumin-sensitized mice are good 54. Humbles AA, Lloyd CM, McMillan SJ, Friend DS, Xanthou G,
models for airway hyperresponsiveness but not acute physiological McKenna EE, Ghiran S, Gerard NP, Yu C, Orkin SH, Gerard C. A
responses to allergen inhalation. Clin Exp Allergy 38(6): 82938, 2007. critical role for eosinophils in allergic airways remodeling. Science 305:
37. Martin TR, Galli SJ, Katona IM, Drazen JM. Role of mast cells in 177679, 2004.
anaphylaxis. Evidence for the importance of mast cells in the cardi- 55. Beuther DA, Weiss ST, Sutherland ER. Obesity and asthma. Am J
opulmonary alterations and death induced by anti-IgE in mice. J Clin Respir Crit Care Med 174: 11219, 2006.
Invest 83: 137583, 1989. 56. Ford ES. The epidemiology of obesity and asthma. J Allergy Clin
38. Chand N, Nolan K, Soa RD, Diamantis W. Changes in aeroallergen- Immunol 115: 897909, 2005. , quiz 910
induced pulmonary mechanics in actively sensitized guinea pig: 57. Shore SA, Johnston RA. Obesity and asthma. Pharmacol Ther 110:
Inhibition by azelastine. Ann Allergy 64: 15154, 1990. 83102, 2006.
39. Eidelman DH, Belloore S, Martin JG. Late airway responses to anti- 58. Shore SA. Obesity and asthma: Implications for treatment. Curr Opin
gen challenge in sensitized inbred rats. Am Rev Respir Dis 137: 1033 Pulm Med 13: 5662, 2007.
37, 1988. 59. Boulet LP, Franssen E. Inuence of obesity on response to uticasone
40. Abraham WM, Oliver W Jr., King MM, Yerger L, Wanner A. Eect with or without salmeterol in moderate asthma. Respir Med 101: 2240
of pharmacologic agents on antigen-induced decreases in specic lung 47, 2007.
conductance in sheep. Am Rev Respir Dis 124: 55458, 1981. 60. Lu FL, Johnston RA, Flynt L, Theman TA, Terry RD, Schwartzman
41. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung IN, Lee A, Shore SA. Increased pulmonary responses to acute ozone
KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, Holgate ST, exposure in obese db/db mice. Am J Physiol Lung Cell Mol Physiol 290:
Fahy JV. Eects of treatment with anti-immunoglobulin E antibody L856l865, 2006.
omalizumab on airway inammation in allergic asthma. Am J Respir 61. Johnston RA, Theman TA, Lu FL, Terry RD, Williams ES Shore SA
Crit Care Med 170: 58393, 2004. (in press) Diet-induced obesity causes innate airway hyperresponsiveness

107
Asthma and COPD: Basic Mechanisms and Clinical Management

to methacholine and enhances ozone induced pulmonary inammation. 83. Fantuzzi G. Adipose tissue, adipokines, and inammation. J Allergy
J Appl Physiol 104: 172735, 2008. Clin Immunol 115: 91119, 2005.
62. Johnston RA, Theman TA, Shore SA. Augmented Responses to Ozone 84. Williams AS, Leung SY, Nath P, Khorasani NM, Bhavsar P, Issa R,
in Obese Carboxypeptidase E-Decient Mice. Am J Physiol Regul Mitchell JA, Adcock IM, Chung KF. Role of TLR2, TLR4, and
Integr Comp Physiol 290: R126R133, 2006. MyD88 in murine ozone-induced airway hyperresponsiveness and
63. Johnston RA, Zhu M, Rivera-Sanchez YM, Lu FL, Theman TA, neutrophilia. J Appl Physiol 103: 118995, 2007.
Flynt L, Shore SA. Allergic airway responses in obese mice. Am J 85. Kadowaki T, Yamauchi T, Kubota N. The physiological and patho-
Respir Crit Care Med 176: 65058, 2007. physiological role of adiponectin and adiponectin receptors in the
64. Rivera-Sanchez YM, Johnston RA, Schwartzman IN, Valone J, peripheral tissues and CNS. FEBS Lett 582: 7480, 2008.
Silverman ES, Fredberg JJ, Shore SA. Dierential eects of ozone on 86. Fantuzzi G. Adiponectin and inammation: Consensus and contro-
airway and tissue mechanics in obese mice. J Appl Physiol 96: 22006, versy. J Allergy Clin Immunol 121: 32630, 2008.
2004. 87. Okamoto Y, Folco EJ, Minami M, Wara AK, Feinberg MW,
65. Shore SA, Rivera-Sanchez YM, Schwartzman IN, Johnston RA. Sukhova GK, Colvin RA, Kihara S, Funahashi T, Luster AD, Libby P.
Responses to ozone are increased in obese mice. J Appl Physiol 95: 938 Adiponectin Inhibits the Production of CXC Receptor Chemokine
45, 2003. Ligands in Macrophages and Reduces T-Lymphocyte Recruitment in
66. Shore SA, Schwartzman IN, Mellema MS, Flynt L, Imrich A, Atherogenesis. Circ Res 121, 2007.
Johnston RA. Eect of leptin on allergic airway responses in mice. 88. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S,
J Allergy Clin Immunol 115: 1039, 2005. Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K,
67. Shore SA, Terry RD, Flynt L, Xu A, Hug C. Adiponectin attenuates Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y,
allergen-induced airway inammation and hyperresponsiveness in Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T,
mice. J Allergy Clin Immunol 118: 38995, 2006. Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors
68. Shore SA. Obesity and asthma: Lessons from animal models. J Appl that mediate antidiabetic metabolic eects. Nature 423: 76269, 2003.
Physiol 102: 51628, 2007. 89. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF.
69. Leibel RL, Chung WK, Chua SC Jr. The molecular genetics of rodent T-cadherin is a receptor for hexameric and high-molecular-weight forms
single gene obesities. J Biol Chem 272: 3193740, 1997. of Acrp30/adiponectin. Proc Natl Acad Sci USA 101: 1030813, 2004.
70. Scherer PE. Adipose tissue: From lipid storage compartment to endo- 90. Snider GL, Lucey EC, Stone PJ. Animal models of emphysema. Am
crine organ. Diabetes 55: 153745, 2006. Rev Respir Dis 133: 14969, 1986.
71. Lang JE, Williams ES, Shore SA. TNF contributes to innate airway 91. Kuhn C, Yu SY, Chraplyvy M, Linder HE, Senior RM. The induc-
hyperresponsiveness in murine obesity. Am J Respir Crit Care Med 175: tion of emphysema with elastase. II: Changes in connective tissue.
A912, 2007. Lab Invest 34: 37280, 1976.
72. Tolbert PE, Mulholland JA, MacIntosh DL, Xu F, Daniels D, 92. Jano A, Sloan B, Weinbaum G, Damiano V, Sandhaus RA, Elias J,
Devine OJ, Carlin BP, Klein M, Dorley J, Butler AJ, Nordenberg DF, Kimbel P. Experimental emphysema induced with puried human
Frumkin H, Ryan PB, White MC. Air quality and pediatric emergency neutrophil elastase: Tissue localization of the instilled protease. Am
room visits for asthma in Atlanta, Georgia, USA. Am J Epidemiol 151: Rev Respir Dis 115: 46178, 1977.
798810, 2000. 93. Kao RC, Wehner NG, Skubitz KM, Gray BH, Hoidal JR. Proteinase
73. Gent JF, Triche EW, Holford TR, Belanger K, Bracken MB, 3. A distinct human polymorphonuclear leukocyte proteinase that
Beckett WS, Leaderer BP. Association of low-level ozone and ne par- produces emphysema in hamsters. J Clin Invest 82: 196373, 1988.
ticles with respiratory symptoms in children with asthma. JAMA 290: 94. Wright JL, Churg A. Cigarette smoke causes physiologic and mor-
185967, 2003. phologic changes of emphysema in the guinea pig. Am Rev Respir Dis
74. Bennett WD, Hazucha MJ, Folinsbee LJ, Bromberg PA, Kissling GE, 142: 142228, 1990.
London SJ. Acute pulmonary function response to ozone in young 95. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD.
adults as a function of body mass index. Inhal Toxicol 19: 114754, Requirement for macrophage elastase for cigarette smoke-induced
2007. emphysema in mice. Science 277: 20024, 1997.
75. Alexee SE, Litonjua AA, Suh H, Sparrow D, Vokonas PS, Schwartz J. 96. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF.
Ozone Exposure and Lung Function: Eect Modied by Obesity and Endothelial cell death and decreased expression of vascular endothe-
Airways Hyperresponsiveness in the VA Normative Aging Study. Chest lial growth factor and vascular endothelial growth factor receptor 2 in
132: 189097, 2007. emphysema. Am J Respir Crit Care Med 163: 73744, 2001.
76. Johnston RA, Williams ES, Shore SA. Airway responses to ozone dur- 97. Aoshiba K, Yokohori N, Nagai A. Alveolar wall apoptosis causes lung
ing the development of obesity. Proc Am Thorac Soc 3: A528, 2006. destruction and emphysematous changes. Am J Respir Cell Mol Biol
77. Lang JE, Williams ES, Mizgerd JP Shore SA (in press) Eect of obes- 28: 55562, 2003.
ity on pulmonary inammation induced by acute ozone exposure: Role 98. Lucey EC, Keane J, Kuang PP, Snider GL, Goldstein RH. Severity
of interleukin-Am J Physiol Lung Cell Mol Physiol 294: L101320, 2008. of elastase-induced emphysema is decreased in tumor necrosis factor-
78. Mito N, Kitada C, Hosoda T, Sato K. Eect of diet-induced obesity alpha and interleukin-1beta receptor-decient mice. Lab Invest 82:
on ovalbumin-specic immune response in a murine asthma model. 7985, 2002.
Metabolism 51: 124146, 2002. 99. Mahadeva R, Shapiro SD. Animal models of pulmonary emphysema.
79. Back M, Sultan A, Ovchinnikova O, Hansson GK. 5-Lipoxygenase- Curr Drug Targets Inamm Allergy 4: 66573, 2005.
activating protein: A potential link between innate and adaptive immu- 100. Massaro GD, Massaro D. Retinoic acid treatment abrogates elastase-
nity in atherosclerosis and adipose tissue inammation. Circ Res 100: induced pulmonary emphysema in rats. Nat Med 3: 67577, 1997.
94649, 2007. 101. Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley
80. Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E, Edelman DG, Marconcini LA, Mecham RP, Senior RM, Shapiro SD. Elastin
JM. Inuence of body mass index on the response to asthma controller fragments drive disease progression in a murine model of emphysema.
agents. Eur Respir J 27: 495503, 2006. J Clin Invest 116: 75359, 2006.
81. Guler N, Kirerleri E, Ones U, Tamay Z, Salmayenli N, Darendeliler F. 102. Snider GL, Lucey EC, Faris B, Jung-Legg Y, Stone PJ, Franzblau C.
Leptin: Does it have any role in childhood asthma? J Allergy Clin Cadmium-chloride-induced air-space enlargement with interstitial
Immunol 114: 25459, 2004. pulmonary brosis is not associated with destruction of lung elastin.
82. Sood A, Ford ES, Camargo CA Jr. Association between leptin and Implications for the pathogenesis of human emphysema. Am Rev
asthma in adults. Thorax 61: 3005, 2006. Respir Dis 137: 91823, 1988.

108
Asthma and COPD: Animal Models 8
103. Shapiro SD. COPD unwound. N Engl J Med 352: 201619, 2005. 117. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A,
104. Wright JL, Postma DS, Kerstjens HA, Timens W, Whittaker P, Hayashi S, Adcock IM, Hogg JC, Barnes PJ. Decreased histone
Churg A. Airway remodeling in the smoke exposed guinea pig model. deacetylase activity in chronic obstructive pulmonary disease. N Engl
Inhal Toxicol 19: 91523, 2007. J Med 352: 196776, 2005.
105. Medler TR, Petrusca DN, Lee PJ, Hubbard WC, Berdyshev EV, 118. Marwick JA, Kirkham PA, Stevenson CS, Danahay H, Giddings J,
Skirball J, Kamocki K, Schuchman E, Tuder RM, Petrache I. Butler K, Donaldson K, Macnee W, Rahman I. Cigarette smoke
Apoptotic sphingolipid signaling by ceramides in lung endothelial alters chromatin remodeling and induces proinammatory genes in
cells. Am J Respir Cell Mol Biol 38(6): 63946, 2008. rat lungs. Am J Respir Cell Mol Biol 31: 63342, 2004.
106. Tang K, Rossiter HB, Wagner PD, Breen EC. Lung-targeted VEGF 119. Parks WC, Shapiro SD. Matrix metalloproteinases in lung biology.
inactivation leads to an emphysema phenotype in mice. J Appl Physiol Respir Res 2: 1019, 2001.
97: 155966, 2004. Discussion 1549. 120. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS,
107. Maeno T, Houghton AM, Quintero PA, Grumelli S, Owen CA, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S. Genetic
Shapiro SD. CD8 T Cells are required for inammation and ablation of Nrf2 enhances susceptibility to cigarette smoke-induced
destruction in cigarette smoke-induced emphysema in mice. emphysema in mice. J Clin Invest 114: 124859, 2004.
J Immunol 178: 809096, 2007. 121. Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ Jr.,
108. van der Strate BW, Postma DS, Brandsma CA, Melgert BN, Chapman HA Jr., Shapiro SD, Elias JA. Inducible targeting of IL-13
Luinge MA, Geerlings M, Hylkema MN, van den Berg A, Timens W, to the adult lung causes matrix metalloproteinase- and cathepsin-
Kerstjens HA. Cigarette smoke-induced emphysema: A role for the B dependent emphysema. J Clin Invest 106: 108193, 2000.
cell? Am J Respir Crit Care Med 173: 75158, 2006. 122. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V,
109. Churg A, Wang RD, Tai H, Wang X, Xie C, Dai J, Shapiro SD, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA.
Wright JL. Macrophage metalloelastase mediates acute cigarette Interleukin-13 induces tissue brosis by selectively stimulating and
smoke-induced inammation via tumor necrosis factor-alpha release. activating transforming growth factor beta(1). J Exp Med 194: 80921,
Am J Respir Crit Care Med 167: 108389, 2003. 2001.
110. Weathington NM, van Houwelingen AH, Noerager BD, Jackson 123. Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G,
PL, Kraneveld AD, Galin FS, Folkerts G, Nijkamp FP, Blalock JE. Glick A, Sheppard D. Loss of integrin alpha(v)beta6-mediated TGF-
A novel peptide CXCR ligand derived from extracellular matrix deg- beta activation causes Mmp12-dependent emphysema. Nature 422:
radation during airway inammation. Nat Med 12: 31723, 2006. 16973, 2003.
111. Saetta M. Airway inammation in chronic obstructive pulmonary 124. Wert SE, Yoshida M, LeVine AM, Ikegami M, Jones T, Ross GF,
disease. Am J Respir Crit Care Med 160: S1720, 1999. Fisher JH, Korfhagen TR, Whitsett JA. Increased metalloproteinase
112. Wang Z, Zheng T, Zhu Z, Homer RJ, Riese RJ, Chapman HA Jr., activity, oxidant production, and emphysema in surfactant protein D
Shapiro SD, Elias JA. Interferon gamma induction of pulmonary gene-inactivated mice. Proc Natl Acad Sci USA 97: 597277, 2000.
emphysema in the adult murine lung. J Exp Med 192: 1587600, 125. Leco KJ, Waterhouse P, Sanchez OH, Gowing KL, Poole AR,
2000. Wakeham A, Mak TW, Khokha R. Spontaneous air space enlargement
113. Grumelli S, Corry DB, Song LZ, Song L, Green L, Huh J, in the lungs of mice lacking tissue inhibitor of metalloproteinases-3
Hacken J, Espada R, Bag R, Lewis DE, Kheradmand F. An immune (TIMP-3). J Clin Invest 108: 81729, 2001.
basis for lung parenchymal destruction in chronic obstructive pulmo- 126. Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK,
nary disease and emphysema. PLoS Med 1: e8, 2004. Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette
114. Robbins C, Franco F, Cernandes M Shapiro SD (in press) Cigarette smoke-induced emphysema in mice. Am J Pathol 163: 232935, 2003.
smoke exposure impairs dendritic cell maturation and T cell prolifera- 127. Henson PM, Cosgrove GP, Vandivier RW. State of the art. Apoptosis
tion in thoracic lymph nodes of mice. J Immunol 180: 66238, 2008. and cell homeostasis in chronic obstructive pulmonary disease. Proc
115. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Moore M, Am Thorac Soc 3: 51216, 2006.
Sullivan A, Nicolls MR, Fontenot AP, Tuder RM, Voelkel NF. An 128. Plantier L, Marchand-Adam S, Antico VG, Boyer L, De Coster C,
animal model of autoimmune emphysema. Am J Respir Crit Care Med Marchal J, Bachoual R, Mailleux A, Boczkowski J, Crestani B.
171: 73442, 2005. Keratinocyte growth factor protects against elastase-induced pul-
116. Lee SH, Goswami S, Grudo A, Song LZ, Bandi V, Goodnight-White S, monary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 293:
Green L, Hacken-Bitar J, Huh J, Bakaeen F, Coxson HO, Cogswell S, L12301239, 2007.
Storness-Bliss C, Corry DB, Kheradmand F. Antielastin autoimmunity
in tobacco smoking-induced emphysema. Nat Med 13: 56769, 2007.

109
Inflammatory Cells
3
PART

and Extracellular
Matrix
Mast Cells and Basophils
9
CHAPTER

Mast cells and basophils rst came to attention George H. Caughey


over a century ago due to their ample stocks ORIGIN AND FATE
of intracellular granules with unusual staining Cardiovascular Research Institute and
characteristics. For many years their origins, nor- Department of Medicine, University of
Mast cells and basophils have shared origins
mal functions, and roles in disease were obscure, but distinct distributions and fates. Mast cells, California at San Francisco, USA
and in some respects remain so. Nonetheless, but not basophils, are normal residents of unin-
knowledge of their biology increased tremen- amed airways. Mature mast cells rarely appear
dously in the past two decades [15]. in blood, whereas mature basophils circulate
Researchers once focused on mast cell and are recruited from blood to sites of allergic
and basophil release of histamine and eicosa- inammation. Both cell types originate from
noids in acute allergic events, which were con- shared progenitors in bone marrow; see Lee
sidered to be a corruption of hypothesized and Krilis [12] for a review. Immature mast cells
normal function of defending against invasion released from marrow circulate briey, exit the
by parasites such as worms and ticks. However, bloodstream to multiple tissue destinations, then
studies in mice now suggest that mast cells dierentiate, adopting a phenotype determined
contribute to innate immune defense against by their microenvironment. Basophils, on the
airway bacteria like mycoplasma [6] and pro- other hand, mature in the marrow, circulate, then
tection from immunologically nonspecic home to sites of inammation if recruited to do
injury, as from venoms [7]. Mast cells and so. Tissue mast cells are not xed in location,
basophils also have the demonstrated potential for they migrate toward airway epithelium after
to inuence immune system development, reg- antigen challenge and trac to lymph nodes
ulation, and initiation of the immune response from sites of antigen exposure. Mast cells prob-
[811]. In some contexts, the overall contri- ably also proliferate in tissues. Conditions such
bution of mast cells is anti-inammatory [6]. as gut parasitosis lead to large local increases in
These roles deviate from traditional concepts mast cells.
of mast cell and basophil participation in adap- Both types of cell survive degranulation
tive responses involving antigen recognition and can restock their secretory granules with
by IgE. mediators. Life span in vivo has not been estab-
In asthma investigations, attention is shift- lished, but in vitro studies predict that basophils
ing from roles of these cells in acute responses are short-lived compared to mast cells, which
to aeroallergen to roles in promoting persist- survive for weeks in culture. In humans, the
ent inammation and remodeling in chronic aggregate mast cell mass is much larger than
disease. Their roles in other obstructive lung that of basophils, which usually comprise 1%
diseases have received less attention, but they of circulating leukocytes. Among mammals,
may indeed contribute to conditions apart from basophil numbers vary widely, ranging from
asthma. numerous in guinea pigs, few in humans and
This chapter summarizes current think- mice, to nearly nonexistent in dogs, in which
ing about roles of mast cells and basophils in they are arguably unimportant. There are genetic
obstructive airway disease. variants of mice with almost no mast cells but

113
Asthma and COPD: Basic Mechanisms and Clinical Management

none with an inherited, selective decit of basophils; thus, it RECRUITMENT


is easier to assess involvement of mast cells than of basophils
in mouse disease models; see Galli [5] for a review.
In asthmatics, increased numbers of basophils and activated
mast cells appear in sputum after allergen challenge [17],
which may reect migration from submucosal sites and blood-
stream, respectively. As noted, mast cell precursors home to
DEVELOPMENT AND HETEROGENEITY tissues even without inammation. Constitutive homing and
epithelial migration may involve responses to proteins such as:
Paucigranular, mast cell-committed progenitors are released C5a;
from marrow expressing surface receptor tyrosine kinase
c-kit and low anity IgG receptor (FcRII) but not high RANTES;
anity IgE receptor, FcRI. In vitro, cells with mature char- IL-8;
acteristics, including FcRI and protease-rich granules, dif-
MIP-1;
ferentiate from progenitors under the inuence of IL-6 and
kit ligand. Presumably, similar events occur in vivo, with kit MCP-1;
ligand produced by endothelial, stromal, and epithelial cells VEGF;
being critical for mast cell survival. Mice with defective
c-kit or its ligand lack mast cells. Their importance to mast fractalkine;
cell development is underscored by gain-of-function c-kit CXCL10;
mutations in systemic mastocytosis and mast cell malig- kit ligand.
nancy, and development of generalized mastocytosis in
response to exogenous kit ligand. The importance of local These may orchestrate movement singly or in combi-
production of kit ligand is suggested by the nding in mice nation. Cultured human mast cells express a broad repertoire
that intratracheal kit ligand provokes mast cell-dependent of chemokine receptors, which diminishes as cells mature,
hyperreactivity [13]. thus limiting mast cell movement after dierentiation at a
In vitro, a variety of cytokines (especially IL-3, -6, -9 tissue site.
and -10, and TGF-1) determines phenotype of matur- Kit ligand is notable in that it is specic for mast
ing mouse mast cells. In the case of IL-9 (a candidate mouse cells in comparison with other leukocytes and is produced
asthma gene), airway overexpression in transgenic mice by airway cells. Mast cell migration into tissues depends
causes eosinophilic inammation and hyperresponsiveness on integrins and other adhesion molecules [18]. Basophils
with mast cell hyperplasia [14]. express an array of chemokine receptors. Chemokines bind-
Mast cells vary in features such as: ing to CCR3 (such as RANTES and eotaxins) may be
especially important [19, 20]. The multiplicity of chemoat-
proteoglycan and protease content; tractants predicts redundant recruiting pathways. Several
metachromasia; chemoattractants also prime or activate one or both types of
cells [20, 21], enhancing their role in asthma pathogenesis
granule ultrastructure; beyond that of recruitment alone.
responses to degranulating stimuli, such as substance P.

These phenotypic variations appear reversible in a given


cell and changeable in cell populations in response to infec-
tion and injury. Classically, rodent mast cells are divided into ACTIVATION
mucosal and connective tissue groups, although the phe-
notype distribution is not strictly bimodal. Human mast cells
are sorted into subsets based on content of granule proteases IgE-dependent activation
[15]. MCT cells express tryptases but not chymase, whereas
MCTC express tryptases and chymase. Occasionally, chymase- Classic mast cell and basophil activation involves docking
only MCC mast cells are seen. Bronchi contain a mixture of of allergens to IgE via FcRI expressed as an assemblage of
types, whereas alveolar interstitium contains predominantly subunits (2) in the plasma membrane. FcRI expres-
MCT. Because mast cells develop and are stimulated in tis- sion is strongly inuenced by the serum level of IgE itself
sues, some variation is due to dierences in maturation, acti- [22]. Aeroallergens with repeating epitopes attach to recep-
vation, or recovery from degranulation. tor chain-bound IgE, bridging receptors. Allergen-driven
Less is known of factors inuencing basophil dier- cross-linking initiates intracellular signaling characterized
entiation. c-Kit appears less important than for mast cells initially by phosphorylation of intracellular immunoreceptor
because mature basophils normally express little or no c-kit tyrosine-based activation motif (ITAM) domains of receptor
and because levels are largely unaected by defects in c-kit and chains. In turn, these recruit and activate nonrecep-
causing profound mast cell decits in mice. Nonetheless, tor tyrosine kinases, especially lyn, syk, and btk, which access
c-kit human basophil-like cells circulate in asthma and pathways leading to exocytosis and synthesis of eicosanoids
atopy and manifest phenotypic changes in which c-kit could and cytokines. Some of these activation pathway proteins
play a role [16]. have emerged as targets for new types of anti-allergic drugs

114
Mast Cells and Basophils 9
[23, 24]. For example, inhibition of syk blocks allergic air- bacterial products (e.g. E. coli FimH);
way inammation in mice [25]. Intriguingly, syk protein is chemokines and lymphokines (e.g. IL-4);
decient in some humans with nonreleaser basophils [26],
although the exact relationship between the nonreleaser phe- kit ligand.
notype and the asthma (or lack thereof ) is not yet clear [27]. These inputs are immunologically nonspecic and
Furthermore, dexamethasone depresses syk activity, which provide the means by which products of activation partici-
may contribute corticosteroid ecacy in asthma [28]. The pate in neurogenic inammation and innate host defense
FcRI chain is not essential in humans but amplies the sig- [31]. They also augment responses to allergen-specic mast
nal. FcRI signals are damped by inhibitory receptors, such as cell activation (see below).
FcRII and gp49, which possess intracellular, immunorecep- Thus, innate and adaptive responses are not mutually
tor tyrosine-based inhibition motif (ITIM) domains [29]. exclusive. C3a, an agent of innate immunity, is an example,
Phosphorylated ITIMs attract tyrosine phos- for C3a receptor-null mice are protected from sequelae of
phatases, such as SHIP, which may inhibit Fc RI signaling airway allergen challenge [32].
by dephosphorylating activated proteins in the signaling It should be noted that human mast cell subpopula-
pathway. tions do not respond uniformly to all stimuli. For example,
FcRIIs importance is particularly compelling [30]. lung mast cells tend to be less responsive than skin mast
When IgG and IgE antibodies are raised against polyvalent cells to substance P [33].
antigen, heterotypic cross-linking of FcRII and Fc RI by
allergen bound to IgG and IgE inhibits signaling by Fc RI.
This may be a means by which blocking antibodies reduce
atopic symptoms after allergen desensitization.
PRIMING AND INHIBITION
IgE-independent activation
Priming describes the response to a substance that does not
Mast cells are activated by multiple nonimmunological release mediators by itself but enhances the eect of another
inputs (Fig. 9.1). Physiological activators include: stimulus, such as cross-linked FcRI. In cultured human
mast cells, priming occurs with allergic cytokines, such as
neuropeptides (e.g. substance P); IL-4 and IL-5 [34], and also with kit ligand and adenos-
purines (adenosine and ATP); ine [35]. Mechanisms of priming may be stimulus-specic
and aect mediator synthesis and release in dierent ways.
byproducts of complement activation (e.g. C3a); Interactions between primers are potentially complex, and, in
eosinophil toxins; the case of IL-4 and -5, may involve autocrine stimulation.

Input Output
Antigen-specific /
Adaptive
Histamine
Antigen Proteases
AgIgG
nonspecific/ Heparin Tryptases, tPA
Innate AgIgE Chymases, Cathepsin G
MHC II
Gelatinases A & B
Substance P Carboxypeptidase A
C3a,C5a Dipeptidylpeptidase I
Escherichia coli FimH Cytokines
Endothelin IL-4, IL-13
IL-5, IL-6, TNF-
Kit ligand Chemokines
IL-8, MIP-1
NGF
Growth factors
ATP bFGF, VEGF, NGF
Adenosine CD40L Eicosanoids
PGD2, LTC4
IL-4
IL-5

Mast cell
FIG. 9.1 Mast cell inputs and outputs. This contains a partial listing of factors influencing human mast cell production of mediators with postulated roles in
acute and chronic airway inflammation in asthma. Inputs are divided into those directly involving immunoglobulin-mediated adaptive responses and those
involving immunologically nonspecific innate/natural immunity.

115
Asthma and COPD: Basic Mechanisms and Clinical Management

In basophils, priming in vitro is especially impressive with heparin delivered into airways in pharmacological doses is
IL-3, which augments release of histamine in response to anti-asthmatic, heparin released from stimulated mast cells
MCP-4 and IL-4 in response to allergen, and is enhanced may attenuate inammatory eects of mediators released
by eotaxin [21]. Basophils harvested from allergic asthmat- from mast cells and other eector cells [45].
ics are primed [36], presumably by exposure to cytokines There is little evidence that human basophils express
in vivo. mediators not also present in mast cells. However, proteins
Priming may serve to activate cells when (and only of unknown function (such as basogranulin) are recognized
when) necessary to protect the host; in asthmatics, dys- by monoclonal antibodies and may be basophil specic
regulated priming may contribute to the pathology of aller- [16, 46].
gic inammation. Fc RI-mediated activation can also be
opposed by physiological inuences, including adrenergic
agonists and inhibitory receptors with ITIMs, as discussed Cytokines and chemokines
above. Inhibition of activation is the basis of emerging strat-
egies to combat allergic disease, including use of adenosine Activated human mast cells express cytokines similar to
receptor antagonists, cytokine and chemokine antagonists, those of TH2 cells, including IL-4, -5, -13, -16, and TNF-
and activators of ITIM containing co-receptors [37]. . In airways in allergic rhinitis or asthma, mast cells are
a substantial fraction of leukocytes expressing these TH2
cytokines [47].
The relative importance of mast cells and basophils
MEDIATORS versus lymphocytes as a source of these cytokines is unclear.
However, mast cells dier from lymphocytes in stor-
ing cytokines in secretory granules. In the case of TNF-
Eicosanoids, histamine, and proteases , release from mast cell stores is a critical determinant of
survival from peritonitis [48]. Asthmatic basophils produce
Stimulated mast cells and basophils release an astonishing prodigious amounts of IL-4 and IL-13 after antigen-specic
variety of stored and newly synthesized mediators. These activation [49]. In mice, basophils may be one of the IL-4-
include prostanoids (Chapter 23), leukotrienes (Chapter producing cell types that skew the immune environment
24), proteases, chemokines (Chapter 26), lymphokines, in the lung toward allergic, Th2-type responses [50, 51].
growth factors (Chapter 29), and nitric oxide (Chapter 30), The importance of IL-4 and IL-13 is strongly supported
the properties and pharmacology of which are considered in by studies in genetically modied mice, which suggest that
other cited chapters and are not reviewed extensively here. airway overproduction causes epithelial hypertrophy, mucus
The principal eicosanoids synthesized after stimula- metaplasia, eosinophilic inammation, and hyperrespon-
tion are PGD2 (whose importance in allergic airway inam- siveness. Cytokine-dependent proliferation of mast cells is
mation is demonstrated in PGD receptor-null mice [38]) complex and is subject to autocrine regulation, as from self-
and LTC4, which is the major target of 5-lipoxygenase stimulation by other types of mediators, such as leukotrienes
inhibitors and leukotriene receptor antagonists. The major [52]. Sustained overproduction of allergic cytokines by mast
granule-associated constituents of human mast cells are cell and basophils may heighten and perpetuate asthmatic
histamine, serine proteases, and proteoglycans (heparin and inammation. Chemokines expressed and secreted by mast
chondroitin). Histamines importance is clearer in upper air- cells include IL-8 and MIP-1, which may recruit eector
way allergic disease, because antihistamines tend to be more leukocytes to sites of inammation [53].
eective in treating rhinitis than asthma. Proteases are the
most abundant proteins in secretory granules [39], though
this may not be true of normal basophils. As noted, human Growth factors
mast cells vary in expression of tryptases and chymase. In
atopic and asthmatic individuals, circulating cells resembling Known cellular growth factors expressed by mast cells
hybrids of basophils and mast cells may express one or both include bFGF [54], VEGF, [55] and nerve growth factor
types of protease [16]. [56]. Less known growth factors are tryptases, which are
Human tryptases are a polymorphic family of trypsin- mitogens for airway broblasts, smooth muscle, and epithe-
like proteases implicated in asthma based on in vitro degrada- lial cells [57] and may inuence endothelial cells to form
tion of bronchodilating peptides, enhancement of bronchial vessels, thereby promoting angiogenesis [58]. Mast cell
contraction, promotion of airway smooth muscle and suben- IL-4 is brogenic when presented in the context of cell-
dothelial broblast growth and collagen production, and pro- to-cell contact [59]. These mediators suggest mechanisms
inammatory properties [40]. Studies in sheep and guinea by which mast cell and basophil mediators promote airway
pigs suggest that inhibitors of tryptases reduce allergen- remodeling in the setting of persistent airway inammation.
induced airway inammation and bronchoconstriction [41]. Recent data from asthmatics suggest that inltration of air-
Chymase is postulated to play roles in asthma by way smooth muscle by mast cells (mastitis) is a phenome-
stimulating gland secretion and promoting airway remod- non specic for asthma, which is to say that it is not seen in
eling via production of angiotensin II and activation of related inammatory airway disorders such as eosinophilic
matrix metalloproteinases [39, 42, 43]. Apart from helping bronchitis [(which unlike asthma is not associated with air-
to package and stabilize proteases [44], the role of heparin way hyperresponsiveness (AHR)] and smoking-associated
and other proteoglycans is less clear. However, because bronchitis [60]. Brightling and colleagues propose that

116
Mast Cells and Basophils 9
airway smooth muscle mastocytosis in asthma is caused by a Anti-IgE joins a growing list of anti-asthmatic drugs inu-
unique asthmatic smooth muscle phenotype, which includes encing mast cells, basophils, and their products. These include:
production of mast cell chemoattractants like CXCL10
[61]. In turn, tryptase and other growth factors produced by corticosteroids (which decrease mast cell numbers) [75];
mast cells recruited to airway smooth muscle may promote cromones;
myocyte hyperplasia or hypertrophy [62, 63]. On the other
hand, Wenzel and colleagues report a positive correlation -adrenergic agonists;
between the chymase-positive subset of distal airway mast theophylline;
cells and lung function [64].
heparin (which inhibits degranulation);
IL-4 antagonists (which inhibit priming) (58);
leukotriene pathway inhibitors.
ROLES IN HOMEOSTASIS Others, eective in animal models, include tryptase
inhibitors [76].
Basophils and mast cells are presumed to exist for reasons Interestingly, mast cell desensitization to chronic
other than to promote sneezing, itching, and wheezing. -agonists used by asthmatics without corticosteroids may
Lacking informative animal models or natural deciency contribute to clinical deterioration [77]. Furthermore, corti-
states, investigators have few direct clues regarding normal costeroids may protect mast cells from desensitization [78].
basophil function. However, compelling evidence of roles Pharmacological evidence of roles for mast cells cor-
for mast cells has emerged from studies by using mast cell- relates with studies indicating activation in allergic airway
decient mice, which suggest critical roles in innate as well as disease [1, 79]. Mast cells release histamine and tryptase
adaptive immune responses, including defense against bacterial into bronchi following allergen challenge [80]. They appear
peritonitis and pneumonia [48, 65]. In similar mouse models degranulated in asthmatic airway, even in stable disease, [81,
(reviewed in [5]), mast cells promote a variety of immunologi- 82] and the percentage of mast cells expressing cytokines
cally nonspecic forms of inammation, for example, ozone- IL-4, IL-5, and TNF- increases [47]. Mast cell and
inicted lung injury [66], providing further evidence that they basophil numbers rise in asthmatic airways and correlate
are activated by IgE-independent pathways. with hyperresponsiveness to acetylcholine [83]. However,
fewer basophils are seen in asthmatic bronchial biopsies
than mast cells or eosinophils, and they are more promi-
nent in cutaneous than airway late-phase reactions [84].
Nonetheless, their arrival coincides with development of
ROLES IN ASTHMA late-phase bronchoconstriction [85]. Airway basophils are
thought to be a source of the late histamine release after
allergen exposure, because this occurs without a correspond-
Animal models ing peak in tryptase, which is more abundant in mast cells.
On the other hand, other granulated leukocytes, including
Several experiments in mice support a role for mast cells in polymorphonuclear neutrophils, also can be sources of air-
asthma-like allergic inammation, including eosinophilia, way histamine [86].
hyperresponsiveness, and epithelial remodeling [14, 6770]. More basophils appear in asthmatic sputum with
Other studies suggest that IgE and mast cells do not make late-phase responses to allergen than in those without such
major contributions (reviewed in [71, 72]). Together, these responses, and their numbers correlate with methacholine
studies reveal that IgE- and mast cell-dependence vary with responsiveness [17]. This supports the hypothesis that mast
strain of mouse, choice of antigen, mode of sensitization and cells and basophils are important in early- and late-phase
challenge, and choice of physiological endpoints. Mast cell responses, respectively. The further hypothesis that these
dependence is easier to detect in mice sensitized and chal- cells promote chronic, persistent asthma is speculative.
lenged locally than systemically, using lower (more physi- However, this notion is supported by the studies summa-
ological) amounts of antigen, without adjuvants. Overall, rized above suggesting that proteases, cytokines, and growth
murine studies suggest that mast cells and IgE are not factors from chronically activated mast cells and basophils
essential for development of eosinophilic inammation but promote airway remodeling and sustain TH2-assisted IgE
do inuence kinetics and magnitude of its expression. production and allergic inammation.

Humans
Notwithstanding some studies questioning its importance ROLES IN CHRONIC OBSTRUCTIVE
in mice, IgEs long-suspected contributions to human
asthma are supported by trials by using anti-IgE antibodies,
PULMONARY DISEASE
which reduce circulating IgE to nearly undetectable levels
and decrease symptoms and corticosteroid use in moder- Several lines of evidence suggest connections between mast
ate, steroid-dependent asthmatics, [73] and rhinitics [74]. cells and chronic obstructive pulmonary disease (COPD) [87].

117
Asthma and COPD: Basic Mechanisms and Clinical Management

Elevated levels of histamine and tryptase in smokers lavage Langerhans cells in response to bacterial peptidoglycan. J Immunol 177:
uid [88] imply that mast cells are activated by smoke. Studies 175562, 2006.
in mice suggest that mast cells promote airway injury and epi- 11. Min B, Le Gros G, Paul WE. Basophils: A potential liaison between
innate and adaptive immunity. Allergol Int 55: 99104, 2006.
thelial remodeling in response to ozone [66], which could
12. Li L, Krilis SA. Mast-cell growth and dierentiation. Allergy 54:
explain some human responses to smoke. Most mast cells 30612, 1999.
close to human bronchial glands express chymase [89], which 13. Campbell E, Hogaboam C, Lincoln P, Lukacs NW. Stem cell factor-
stimulates gland cell secretion [42] and may promote sputum induced airway hyperreactivity in allergic and normal mice. Am J Pathol
production in bronchitis. 154: 125965, 1999.
Conceivably, mast cells contribute to emphysema- 14. Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of inter-
tous lung destruction by secreting matrix altering proteases, leukin 9 in the lungs of transgenic mice causes airway inammation,
for example chymase, tryptases, gelatinases, plasminogen mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med
activator, and dipeptidyl peptidase I [39]. Some investiga- 188: 130720, 1998.
tors nd increased mast cell numbers in proximal airways 15. Irani AA, Schechter NM, Craig SS et al. Two types of human mast
cells that have distinct neutral protease compositions. Proc Natl Acad
of asymptomatic smokers with mild COPD [90], although
Sci USA 83: 446468, 1986.
the relationship to lung function is less clear. Overall, evi- 16. Li L, Li Y, Reddel SW et al. Identication of basophilic cells that
dence of mast cell involvement in asthma is more compel- express mast cell granule proteases in the peripheral blood of asthma,
ling, although further investigation of connections between allergy, and drug-reactive patients. J Immunol 161: 507986, 1998.
mast cells and COPD is warranted. 17. Gauvreau GM, Lee JM, Watson RM et al. Increased numbers of
both airway basophils and mast cells in sputum after allergen inhala-
tion challenge of atopic asthmatics. Am J Respir Crit Care Med 161:
147378, 2000.
18. Hamawy MM, Mergenhagen SE, Siraganian RP. Adhesion molecules
SUMMARY as regulators of mast-cell and basophil function. Immunol Today 15:
6266, 1994.
19. Uguccioni M, Mackay CR, Ochensberger B et al. High expression of
Mast cells protect from certain types of infection and injury the chemokine receptor CCR3 in human blood basophils. Role in acti-
by contributing to innate and adaptive immune responses. vation by eotaxin, MCP-4, and other chemokines. J Clin Invest 100:
The homeostatic roles of basophils are less clear. Both cell 113743, 1997.
types participate in the pathology of atopy and asthma by 20. Ochensberger B, Tassera L, Bifrare D et al. Regulation of cytokine expres-
deploying an arsenal of inammatory mediators, including sion and leukotriene formation in human basophils by growth factors,
proteases, growth factors, chemokines, and TH2 cytokines. chemokines and chemotactic agonists. Eur J Immunol 29: 1122, 1999.
Mast cells, being permanent airway residents, are more likely 21. Devouassoux G, Metcalfe DD, Prussin C. Eotaxin potentiates antigen-
to encounter aeroallergens rst and to participate in acute dependent basophil IL-4 production. J Immunol 163: 287782, 1999.
22. Saini SS, Klion AD, Holland SM et al. The relationship between serum
responses. Basophils, because of the time lag of recruitment,
IgE and surface levels of FcR on human leukocytes in various diseases:
may be more important in late-phase responses. Correlation of expression with FcepsilonRI on basophils but not on
Support is mounting for the hypothesis that both types monocytes or eosinophils. J Allergy Clin Immunol 106: 51420, 2000.
of cells magnify the pathology of persistent inammation in 23. Oliver JM, Kepley CL, Ortega E, Wilson BS. Immunologically medi-
chronic asthma, including stimulation of IgE production, ated signaling in basophils and mast cells: nding therapeutic targets
recruitment of eosinophils, and remodeling of epithelium. for allergic diseases in the human FcR1 signaling pathway. Immuno-
pharmacology 48: 26981, 2000.
24. Barnes PJ. Novel signal transduction modulators for the treatment of
airway diseases. Pharmacol Ther 109: 23845, 2006.
References 25. Matsubara S, Li G, Takeda K et al. Inhibition of spleen tyrosine kinase
prevents mast cell activation and airway hyperresponsiveness. Am J
1. Kaliner M. Asthma and mast cell activation. J Allergy Clin Immunol 83: Respir Crit Care Med 173: 5663, 2006.
51020, 1989. 26. Kepley CL. Antigen-induced reduction in mast cell and basophil func-
2. Schulman ES. The role of mast cells in inammatory responses in the tional responses due to reduced Syk protein levels. Int Arch Allergy
lung. Crit Rev Immunol 13: 3570, 1993. Immunol 138: 2939, 2005.
3. Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev 77: 27. Youssef LA, Schuyler M, Gilmartin L et al. Histamine release from the
103379, 1997. basophils of control and asthmatic subjects and a comparison of gene
4. Dvorak AM. Cell biology of the basophil. Int Rev Cytol 180: 87236, expression between releaser and nonreleaser basophils. J Immunol
1998. 178: 458494, 2007.
5. Galli SJ. Mast cells and basophils. Curr Opin Hematol 7: 3239, 2000. 28. Hiragun T, Peng Z, Beaven MA. Cutting edge: dexamethasone nega-
6. Xu X, Zhang D, Lyubynska N et al. Mast cells protect mice from myc- tively regulates Syk in mast cells by up-regulating SRC-like adaptor
oplasma pneumonia. Am J Respir Crit Care Med 173: 21925, 2006. protein. J Immunol 177: 204750, 2006.
7. Metz M, Piliponsky AM, Chen CC et al. Mast cells can enhance 29. Ott VL, Cambier JC. Activating and inhibitory signaling in mast cells:
resistance to snake and honeybee venoms. Science 313: 52630, 2006. New opportunities for therapeutic intervention?. J Allergy Clin Immunol
8. Nakae S, Suto H, Kakurai M et al. Mast cells enhance T cell activation: 106: 42940, 2000.
Importance of mast cell-derived TNF. Proc Natl Acad Sci USA 102: 30. Takai T, Ono M, Hikida M et al. Augmented humoral and anaphylac-
6467472, 2005. tic responses in FcRII-decient mice. Nature 379: 34649, 1996.
9. Lu LF, Lind EF, Gondek DC et al. Mast cells are essential intermedi- 31. Galli SJ, Wershil BK. The two faces of the mast cell. Nature 381: 2122,
aries in regulatory T-cell tolerance. Nature 442: 9971002, 2006. 1996.
10. Jawdat DM, Rowden G, Marshall JS. Mast cells have a pivotal role in 32. Humbles AA, Lu B, Nilsson CA et al. A role for the C3a anaphylatoxin
TNF-independent lymph node hypertrophy and the mobilization of receptor in the eector phase of asthma. Nature 406: 9981001, 2000.

118
Mast Cells and Basophils 9
33. Church MK, Lowman MA, Robinson C et al. Interaction of neuropep- 56. Nilsson G, Forsberg-Nilsson K, Xiang Z et al. Human mast cells
tides with human mast cells. Int Arch Allergy Immunol 88: 7078, 1989. express functional TrkA and are a source of nerve growth factor. Eur J
34. Ochi H, De Jesus NH, Hsieh FH et al. IL-4 and -5 prime human mast Immunol 27: 2295301, 1997.
cells for dierent proles of IgE-dependent cytokine production. Proc 57. Cairns JA, Walls AF. Mast cell tryptase is a mitogen for epithelial cells-
Natl Acad Sci U. S A 97: 1050913, 2000. Stimulation of IL-8 production and intercellular adhesion molecule-1
35. Marquardt DL. Adenosine. In: Barnes PJ, Grunstein MM, Le AR, expression. J Immunol 156: 27583, 1996.
Woolcock AJ (eds). Asthma, Philadelphia: Lippincott-Raven, 1997. 58. Coussens LM, Raymond WW, Bergers G et al. Inammatory mast
36. Lie WJ, Knol EF, Mul FP et al. Basophils from patients with allergic cells upregulate angiogenesis during squamous epithelial carcinogen-
asthma show a primed phenotype. J Allergy Clin Immunol 104: 10007, esis. Genes Dev 13: 138297, 1999.
1999. 59. Trautmann A, Krohne G, Brocker EB, Klein CE. Human mast cells
37. Bingham CO III, Austen KF. Mast-cell responses in the development augment broblast proliferation by heterotypic cell-cell adhesion and
of asthma. J Allergy Clin Immunol 105: S527S534, 2000. action of IL-4. J Immunol 160: 505357, 1998.
38. Matsuoka T, Hirata M, Tanaka H et al. Prostaglandin D2 as a mediator 60. Brightling CE, Bradding P, Symon FA et al. Mast-cell inltration of
of allergic asthma. Science 287: 201317, 2000. airway smooth muscle in asthma. N Engl J Med 346: 1699705, 2000.
39. Caughey GH (ed.), Mast Cell Proteases in Immunology and Biology. New 61. Brightling CE, Ammit AJ, Kaur D et al. The CXCL10/CXCR3 axis
York: Marcel Dekker, Inc, 1995. mediates human lung mast cell migration to asthmatic airway smooth
40. Caughey GH. Of mites and men: Trypsin-like proteases in the lungs. muscle. Am J Respir Crit Care Med 171: 110308, 2005.
Am J Respir Cell Mol Biol 16: 62128, 1997. 62. Brown JK, Jones CA, Rooney LA, Caughey GH. Mast cell tryptase
41. Clark JM, Abraham WM, Fishman CE et al. Tryptase inhibitors block activates extracellular-regulated kinases (p44/p42) in airway smooth-
allergen-induced airway and inammatory responses in allergic sheep. muscle cells: Importance of proteolytic events, time course, and role in
Am J Resp Crit Care Med 152: 207683, 1995. mediating mitogenesis. Am J Respir Cell Mol Biol 24: 14654, 2001.
42. Sommerho CP, Caughey GH, Finkbeiner WE et al. Mast cell chy- 63. Caughey GH. Mast cell tryptases and chymases in inammation and
mase. A potent secretagogue for airway gland serous cells. J Immunol host defense. Immunol Rev 217: 14154, 2007.
142: 245056, 1989. 64. Balzar S, Chu HW, Strand M, Wenzel S. Relationship of small airway
43. Fang KC, Raymond WW, Blount JL, Caughey GH. Dog mast cell chymase-positive mast cells and lung function in severe asthma. Am J
-chymase activates progelatinase B by cleaving the Phe88-Phe89 Respir Crit Care Med 171: 43139, 2005.
and Phe91-Glu92 bonds of the catalytic domain. J Biol Chem 272: 65. Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of
2562835, 1997. neutrophil inux and bacterial clearance at sites of infection through
44. Humphries DE, Wong GW, Friend DS et al. Heparin is essential for TNF-. Nature 381: 7780, 1996.
the storage of specic granule proteases in mast cells. Nature 400: 769 66. Longphre M, Zhang LY, Harkema JR, Kleeberger SR. Mast cells con-
72, 1999. tribute to O3-induced epithelial damage and proliferation in nasal and
45. Ahmed T, Syriste T, Mendelssohn R et al. Heparin prevents antigen- bronchial airways of mice. J Appl Physiol 80: 132230, 1996.
induced airway hyperresponsiveness: Interference with IP3-mediated 67. Martin TR, Takeishi T, Katz HR et al. Mast cell activation enhances
mast cell degranulation? J Appl Physiol 76: 893901, 1994. airway responsiveness to methacholine in the mouse. J Clin Invest 91:
46. McEuen AR, Buckley MG, Compton SJ, Walls AF. Development and 117682, 1993.
characterization of a monoclonal antibody specic for human basophils 68. Kung TT, Stelts D, Zurcher JA et al. Mast cells modulate allergic pul-
and the identication of a unique secretory product of basophil activa- monary eosinophilia in mice. Am J Respir Cell Mol Biol 12: 4049, 1995.
tion. Lab Invest 79: 2738, 1999. 69. Kobayashi T, Miura T, Haba T et al. An essential role of mast cells in
47. Bradding P, Roberts JA, Britten KM et al. Interleukin-4, -5, and -6 and the development of airway hyperresponsiveness in a murine asthma
tumor necrosis factor- in normal and asthmatic airways: Evidence for model. J Immunol 164: 385561, 2000.
the human mast cell as a source of these cytokines. Am J Repir Cell Mol 70. Williams CM, Galli SJ. Mast cells can amplify airway reactivity and
Biol 10: 47180, 1994. features of chronic inammation in an asthma model in mice. J Exp
48. Echtenacher B, Mnnel DN, Hltner L. Critical protective role of mast Med 192: 45562, 2000.
cells in a model of acute septic peritonitis. Nature 381: 7577, 1996. 71. Hamelmann E, Tadeda K, Oshiba A, Gelfand EW. Role of IgE in the
49. Devouassoux G, Foster B, Scott LM et al. Frequency and characteri- development of allergic airway inammation and airway hyperrespon-
zation of antigen-specic IL-4- and IL-13- producing basophils and sivenessa murine model. Allergy 54: 297305, 1999.
T cells in peripheral blood of healthy and asthmatic subjects. J Allergy 72. Galli SJ. Commentary: Complexity and redundancy in the pathogen-
Clin Immunol 104: 81119, 1999. esis of asthma: Reassessing the roles of mast cells and T cells. J Exp
50. Min B, Prout M, Hu-Li J et al. Basophils produce IL-4 and accumu- Med 186: 34347, 1997.
late in tissues after infection with a Th2-inducing parasite. J Exp Med 73. Milgrom H, Fick RB Jr., Su JQ et al. Treatment of allergic asthma with
200: 50717, 2004. monoclonal anti-IgE antibody. N Engl J Med 341: 196673, 1999.
51. Voehringer D, Shinkai K, Locksley RM. Type 2 immunity reects 74. Adelroth E, Rak S, Haahtela T et al. Recombinant humanized mAb-
orchestrated recruitment of cells committed to IL-4 production. E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhini-
Immunity 20: 26777, 2004. tis. J Allergy Clin Immunol 106: 25359, 2000.
52. Jiang Y, Kanaoka Y, Feng C, Nocka K, Rao S, Boyce JA. Cutting edge: 75. Djukanovic R, Wilson JW, Britten KM et al. Quantitation of mast
Interleukin 4-dependent mast cell proliferation requires autocrine/ cells and eosinophils in the bronchial mucosa of symptomatic atopic
intracrine cysteinyl leukotriene-induced signaling. J Immunol 177: asthmatics and healthy control subjects using immunohistochemistry.
275559, 2006. Am Rev Respir Dis 142: 86371, 1990.
53. Moller A, Lippert U, Lissmann D et al. Human mast cell produce 76. Clark JM, Moore WR, Fishman CE et al. A novel tryptase inhibitor,
IL-8. J Immunol 151: 326166, 1993. APC 366, inhibits allergen-induced airway and inammatory responses
54. Powers MR, Qu Z, LaGesse PC et al. Expression of basic broblast in allergic sheep. Am J Respir Crit Care Med 152: 207683, 1995.
growth factor in nasal polyps. Ann Otol Rhinol Laryngol 107: 89197, 77. Swystun VA, Gordon JR, Davis EB et al. Mast cell tryptase release and
1998. asthmatic responses to allergen increase with regular use of salbutamol.
55. Boesiger J, Tsai M, Maurer M et al. Mast cells can secrete vascular J Allergy Clin Immunol 106: 5764, 2000.
permeability factor/vascular endothelial cell growth factor and exhibit 78. Chong LK, Drury DEJ, Dummer JF et al. Protection by dexametha-
enhanced release after IgE-dependent upregulation of Fc epsilon recep- sone of the functional desensitization to 2-adrenoceptor-mediated
tor I expression. J Exp Med 188: 113545, 1998. responses in human lung mast cells. Br J Pharmacol 121: 71722, 1997.

119
Asthma and COPD: Basic Mechanisms and Clinical Management

79. Bousquet J, Jeery PK, Busse WW et al. Asthma. From bronchocon- 85. Guo CB, Liu MC, Galli SJ et al. Identication of IgE-bearing cells in
striction to airways inammation and remodeling. Am J Respir Crit the late-phase response to antigen in the lung as basophils. Am J Respir
Care Med 161: 172045, 2000. Cell Mol Biol 10: 38490, 1994.
80. Wenzel SE, Fowler A, Schwartz LB. Activation of pulmonary mast 86. Xu X, Zhang D, Zhang H et al. Neutrophil histamine contributes to
cells by bronchoalveolar allergen challenge. In vivo release of hista- inammation in mycoplasma pneumonia. J Exp Med 203: 290717,
mine and tryptase in atopic subjects with and without asthma. Am Rev 2006.
Respir Dis 137: 10028, 1998. 87. Pesci A, Rossi GA, Bertorelli G et al. Mast cells in the airway lumen
81. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the and bronchial mucosa of patients with chronic bronchitis. Am J Respir
bronchi in mild asthma and after bronchial provocation. Am Rev Respir Crit Care Med 149: 131116, 1994.
Dis 139: 80617, 1989. 88. Kalenderian R, Raju L, Roth W et al. Elevated histamine and tryptase
82. Pesci A, Foresi A, Bertorelli G et al. Histochemical characteristics and levels in smokers bronchoalveolar lavage uid. Do lung mast cells con-
degranulation of mast cells in epithelium and lamina propria of bron- tribute to smokers emphysema? Chest 94: 11319, 1988.
chial biopsies from asthmatic and normal subjects. Am Rev Respir Dis 89. Matin R, Tam EK, Nadel JA, Caughey GH. Distribution of chymase-
147: 68489, 1993. containing mast cells in human bronchi. J Histochem Cytochem 40:
83. Koshino T, Arai Y, Miyamoto Y et al. Airway basophil and mast cell 78186, 1992.
density in patients with bronchial asthma: Relationship to bronchial 90. Ekberg-Jansson A, Amin K, Bake B et al. Bronchial mucosal mast
hyperresponsiveness. J Asthma 33: 8995, 1996. cells in asymptomatic smokers relation to structure, lung function and
84. Macfarlane AJ, Kon OM, Smith SJ et al. Basophils, eosinophils, and emphysema. Respir Med 99: 7583, 2005.
mast cells in atopic and nonatopic asthma and in late-phase allergic
reactions in the lung and skin. J Allergy Clin Immunol 105: 99107, 2000.

120
Dendritic Cells in Asthma and COPD
10
CHAPTER

INTRODUCTION situation and the therapeutic potential of novel Bart N. Lambrecht1,2


ndings will be discussed where possible.
and Guy G. Brusselle2
The lung contains many subsets of dendritic cells 1
Department of Respiratory Medicine,
(DCs) that are distributed in various anatomi- University Hospital Ghent, Belgium
cal compartments. In homeostatic conditions, a LUNG DC SUBSETS IN 2
Department of Pulmonary Medicine,
ne-tuned balance exists between plasmacytoid
and myeloid DCs necessary for maintaining
MOUSE AND MAN Erasmus University Medical Center,
Rotterdam, The Netherlands
tolerance to inhaled antigen and for avoiding
overt inammation. These subsets of DCs also It has long been established that the various
play important roles in establishment of airway lung compartments (conducting airways, lung
inammation seen in asthma and COPD. Based parenchyma, alveolar compartment, pleura) con-
on these new insights on airway DC biology, tain numerous DCs, of which the precise line-
several approaches that interfere with DC func- age or origin have been poorly dened. Recently
tion show potential as new intervention strate- however, many groups have rened the ways
gies for these ever increasing diseases. in which lung DCs should be studied, both in
Obstructive airway disease, broadly mouse [25] and in human [6, 7]. It is clear
divided clinically into asthma or COPD, is a that dierent DC subsets can be found in the
signicant cause of morbidity and mortality. In lung, each with functional specialization. In the
allergic asthma, allergen-specic T-helper type mouse, all of these express the integrin CD11c
2 (Th2) cells produce key cytokines like IL-4, and the subsets are further dened on the basis
IL-5, and IL-13 that regulate the synthesis of of the expression of the myeloid marker CD11b,
allergen-specic IgE and control tissue eosi- as well as anatomical location in the lung. The
nophilic airway inammation and remodeling trachea and large conducting airways have a
of the airways. In the lungs of COPD patients, well-developed network of intraepithelial DCs,
predominantly CD8 lymphocytes and neu- even in steady-state conditions. These cells in
trophilic airway inammation are seen, con- some way resemble skin Langerhans cells,
comitant with remodeling of small airways and and have been shown to express langerin and
the destruction of distal air spaces characteris- CD103 while lacking expression of CD11b [4,
tic of emphysema. It is increasingly clear that 8]. In the submucosa of the conducting airways,
DCs are essential for inducing activation and CD103CD11bCD11c myeloid DCs can be
dierentiation of not only nave but also eec- found, particularly under conditions of inam-
tor CD4 T- and CD8 T-cells in response to mation, and these cells are particularly suited for
inhaled antigen, and it has been well established priming and restimulating eector CD4 cells
that these cells play a pivotal role in the initia- in the lung [8, 9]. The lung interstitium that is
tion and maintenance phase of airway inam- accessible by enzymatic digestion also contains
mation [1]. In this chapter, we will highlight the CD11b and CD11b DCs that access the
recent discoveries in airway DC biology with alveolar lumen and migrate to the mediastinal
special emphasis on mouse models of asthma lymph nodes (MLN) [2, 5, 10]. It should be
and COPD. The applicability to the human noted that this population is contaminated with

121
Asthma and COPD: Basic Mechanisms and Clinical Management

DCs lining the small intrapulmonary bronchioles, as well as and then migrating to the MLN in a CCR7-dependent way
those lining the vessel walls. In the nearby alveolar lumen, [5, 8, 10]. It is still a matter of debate, however, whether the
CD11chi alveolar macrophages control the function of these uptake and transport of inhaled antigen occurs exclusively
interstitial DCs. Plasmacytoid DCs are CD11bCD11cint by alveolar wall DCs, by intraepithelial DCs lining the large
cells expressing SiglecH and bone marrow stromal Ag-1 conducting airways or by both [2, 5]. Another controversial
(recognized by the moAbs mPDCA-1 or 120G8). In the issue is the location and extent by which plasmacytoid DCs
lungs, pDCs are predominantly found in the lung intersti- take up inhaled antigen. Two reports describe that within
tium and produce large amounts of IFN in response to 2448 h following exposure of inhaled uorescently labeled
triggering by CpG motifs or viral infection ex vivo [11]. Ag, almost 5060% of pDCs are antigen-positive [11, 16],
The exact denition of the dierent DC subtypes in whereas another report saw only a minor percentage of Ag
the human lung is incomplete and a subject of controversy. uptake in this subset [5]. It remains to be demonstrated
Two groups identied myeloid DC and plasmacytoid DC if pDCs take up antigen in the periphery of the lung and
in single cell suspensions from digested human lung tis- subsequently migrate, whether they get their antigen from
sue by ow cytometry, using the blood dendritic cell anti- another migratory DC [17], or whether they take up free
gen markers (BDCA) 1 through 3 [7, 12]. The Cluster of aerent lymph while residing in the lymph node. How
Dierentiation (CD) nomenclature of these BDCA mark- much antigen crosses the epithelial barrier passively in the
ers is as follows: BDCA1 CD1c, BDCA2 CD303, and absence of DC uptake is unknown, but it heavily depends
BDCA3 CD141. Within the low autouorescent mono- on the molecular weight of the Ag, its dose, as well as the
nuclear cells of the lung digests, cells that were positive potential to disrupt epithelial tight junctions. Control of
for the lineage markers, that is, CD3, CD19, CD20, and epithelial barrier function could be under important genetic
CD56, were excluded. Within the lineage negative pulmo- control as well, as many of the gene polymorphisms associ-
nary mononuclear cells, myeloid DC type 1 were character- ated with atopy in humans control epithelial integrity (e.g.
ized as CD1c/HLA-DR cells, myeloid DC type 2 were Spink5, S100 family). It is similarly possible that Ag uptake
characterized as CD141/HLA-DR cells, and plasmacy- by lung pDCs would be facilitated by the presence of Ag-
toid DC were characterized as CD303/CD123 cells. In specic immunoglobulins acting on Fc receptors, thus
vitro studies suggest that Langerhans type DC (that are enhancing endocytosis [18].
Langerin, CD1a, and Birbeck granule positive) derive
from myeloid DC precursors that are CD1c and CD1a
[13], and others have shown that Langerhans-type DC can
be generated from monocytes under the inuence of inter-
leukin-15 [14]. It is unclear whether dierences in terms of ROLE OF DCS IN ASTHMA
expression of surface markers reect separate stages of dif-
ferentiation of the DC, rather than dierent sublineages. Outcome of antigen inhalation depends
It is tempting to speculate that, within these DC subsets,
carrying dierent surface markers, functional specialization on the functional state of myeloid and
does occur. Indeed, pulmonary myeloid DC types 1 and 2 plasmacytoid DCs
were shown to release proinammatory cytokines (TNF-,
IL-1, IL-6, and IL-8) in response to Toll-like receptor-2 The usual outcome of inhalation of harmless protein antigen
(TLR-2) and TLR-4 ligands, whereas plasmacytoid DC in the lungs is immunological tolerance (see Fig. 10.1 for a
released high amounts of interferon- in response to the model depicting cellular interactions). As a result, when the
TLR-9 ligand CpG oligonucleotides [6]. Moreover, mye- antigen is subsequently given to mice in an adjuvant setting
loid DC type 1 was shown to be strong inducers of T-cell (e.g. in combination with the Th2 adjuvant alum) it no longer
proliferation in a mixed leukocyte reaction, while plasmacy- induces an immunological response that leads to eector
toid DC induced little T-cell proliferation and myeloid DC cells causing inammation [11, 19]. Inhalational tolerance is
type 2 had an intermediate T-cell-stimulatory capacity [6]. mediated in part by deletion of Ag reactive T-cells as well as
How, where, and by which DC subset inhaled anti- induction and/or expansion of regulatory T-cells in the medi-
gen is sampled from the airway lumen has been a matter astinal nodes [17, 1921]. The latter type of tolerance is domi-
of debate. Jahnsen demonstrated that, analogous to that nant and can be transferred to other mice by adoptive transfer.
reported in the gut, a subset of rat airway intraepithelial Induction of tolerance to inhaled antigen is a function of lung
DCs extend their processes into the airway lumen. This DC subsets that migrate from the lung in a CCR7-dependent
periscope up function is constitutively expressed within way [17]. It is often claimed that induction of tolerance is a
the airway mucosal DC population, providing a mechanism function of immature DCs, meaning that these cells lack the
for continuous immune surveillance of the airway lumi- expression of high levels of major histocompatibility complex
nal surface in the absence of danger signals [15]. In the (MHC), adhesion, and co-stimulatory molecules, However,
mouse, CD103CD11b intraepithelial DCs express the Reis and Sousa recently argued that the term mature DC
tight junction proteins claudin-1, claudin-7, and zonula-2, should be reserved for those DCs that have the potential to
allowing the sampling of airway luminal contents whereas generate eector T-cells, and that expression of costimulatory
keeping the epithelial barrier function intact [4]. This subset molecules by DCs does not exclude the possibility that toler-
is also found in the alveolar septa, and DCs lining the alve- ance would be induced [22]. In the lungs, inhaled tolerance is
olar wall can take up inhaled harmless ovalbumin (OVA) or dependent on signals delivered by CD86 and/or ICOS-L on
bacterial anthrax spores by forming intra-alveolar extensions DCs, supporting this view [20].

122
Dendritic Cells in Asthma and COPD 10
Microbial
cofactors

Complement Other baseline


Harmless activation agonist
antigens

C5aR
Partially mature
? CD80/86/ICOSL
Abortive proliferation
MARCO Treg formation
SR-AI/II
mDC Naive
Cox-2-derived T
Mph
PGs Negative
signal

Treg
Immature
pDC high PDL-1
2,3-IDO
Negative
signal X
GITR Treg
CTLA4

FIG. 10.1 Dendritic cell function following inhalation of harmless antigen in homeostatic conditions. When an inhaled antigen reaches the deeper airways
and it is not cleared by mucociliary transport or by macrophages, it will be taken up by airway DCs. Both mDCs and pDCs take up antigen. mDCs seem to
do this in the periphery, whereas pDCs only do this in the mediastinal nodes. In baseline conditions, the mDCs that reach the nodes are only partly mature
and the T-cell response that they induce is characterized mainly by division but not by differentiation to effector cells. Eventually many dividing cells die.
Additionally, mDCs induce Treg cells that suppress inflammation. At the same time, the pDCs control the level of activity of the mDCs so that these cells are
kept in a quiescent state. This function of pDCs is controlled by Treg control occurring via GITRGIRL ligand and CLTA4CD80/86 interactions. The signals
involved are not precisely known but could involve IDO, or some surface expressed ligand on pDCs (programmed death ligand-1, PDL1). The function of
mDCs is constantly kept in check among others by tonic inhibition by cyclooxygenase-2 (Cox-2) derived prostaglandins (PGs), as well as by complement
activation acting on the C5a receptor (C5a). The precise ligand for the class A scavenger receptors (MARCO and SR-AI/II) are not known.

Conventional lung DCs (either CD11b or CD11b) When pDCs are depleted from the lungs, inhaled tol-
are necessary for tolerance induction [17] but are also erance is abolished, and consequently pDC/mDC balance
responsible for inducing Th2 sensitization, providing there is in the lung is tightly regulated among others by the cytokine
some form of activation (either LPS or TNF) [23] leading osteopontin as well as complement C5a [11, 16, 28, 29].
to functional DC dierentiation and their capacity to prime How exactly pDC depletion leads to sensitization is still
Th2 eector cells (see Fig. 10.2 for a model depicting cellular unsolved, but in vitro and in vivo data suggest that pDCs
interactions leading to Th2 sensitization in the airways). In directly suppress the potential of mDCs to generate eector
further support, Th2 sensitization can be induced by adop- T-cells [11, 29]. Plasmacytoid DCs can also stimulate the
tive intratracheal transfer of GM-CSF-cultured bone mar- formation of Treg cells, possibly in an ICOS-L-dependent
row DCs, most closely resembling mature monocyte-derived way [11, 30]. Tregs expressing GITR could also induce
CD11b DCs, but not by Flt3L-cultured bone marrow- the production of the tryptophan catabolizing enzyme
derived DCs that more resemble the immature steady-state indoleamine 2,3-dioxygenase (IDO) through reverse sign-
DCs resident in the lymph nodes and spleen [11]. As acti- aling in pDCs [31]. In mice depleted of pDCs, there was
vation of lung DCs is the common event leading to Th2 endogenous release of extracellular adenosine triphosphate
sensitization, it is likely that under homeostatic conditions, (ATP) responsible for inducing mDC maturation and
the degree of DC maturation is, therefore, constantly kept in Th2 skewing potential. Th2 sensitization to inhaled OVA
check. One such pathway of tonic DC suppression seems to was abolished when ATP signaling was blocked using the
involve COX-2-derived prostaglandins or their metabolites, broad spectrum P2X and P2Y receptor antagonist suramin.
most likely derived from nearby alveolar macrophages [24]. On the contrary, a non-degradable form of ATP was able
Chimeric mice in which the PGD2 receptor DP1 was selec- to break inhalation tolerance to OVA [32]. At present, it
tively deleted on hematopoietic cells, demonstrated sponta- is unclear how purinergic receptor triggering on DCs pro-
neous maturation of lung mDCs and subsequently, response motes Th2 development, but it could involve the formation
to harmless antigen was greatly enhanced, suggesting tonic of the inammasome, a multi-protein complex that leads to
inhibition of DC function by PGD2 in the lung [25]. When activation of caspase 1 and processing and release of IL-1,
exposed to selective PGD2 agonists, myeloid DCs induced IL-18, and possibly IL-33. One possibility is also that ATP
the formation of Foxp3 Ag-specic Tregs that subsequently indirectly inuences DC function via the modication of
suppressed airway inammation. A similar mechanism on mast cell and eosinophil function. Mast cells (e.g. through
DCs was found for stable PGI2 analogs [26, 27]. release of cytokines, PGD2 or sphingosine metabolites) [33]

123
Asthma and COPD: Basic Mechanisms and Clinical Management

Epithelial activation:
TLR agonist
Proteolytic allergen
Diesel, cigarette smoke

TSLP
GM-CSF
IL1
Inducing mDC maturation:
Proteolytic allergens
Low dose TLR agonist
Loss of Treg control (Run 3/) Mature
CCR4
Alum/diesel adjuvant high CD80/86
Th2 effectors
Viral infection CCL17/CCL22
Interleukin 17?
Endogenous danger signals
(ATP, TNF-, HMGB1 ?, uric acid ?)

mDC Naive
T
mDC

Mature
high CD80/86
pDC
Increasing mDC/pDC balance: pos
GM-CSF overexpression signal?
C5aR blockade IFN-
Osteopontin Loss of pDC tolerogenic function:
Cholera toxin Viral infection
Artificial injection of mDCs Injection of pDC depleting antibody
Osteopontin

FIG. 10.2 Model of dendritic cell function during Th2 sensitization. Several known risk factors for atopy have been shown to interfere with DC function in
the airways. Also, several experimental models have been developed in which sensitization occurs even after inhalation of harmless antigens to the lung,
providing there is some form of DC activation. In these models, respiratory tolerance is broken. Some models have induced a shift in the pDC/mDC balance,
and consequently mDCs induce priming because they are no longer suppressed by adequate numbers of pDCs. Activated mDCs also produce chemokines
like CCL17 or CCL22 to further attract Th2 cells into the response. Some adjuvants induce proper activation of mDCs (yet not sufficient to induce IL-12)
so that they now induce effector Th2 cells rather than regulatory T-cells. Some stimuli, like concomitant viral infection, might have an additional effect by
inducing maturation of pDCs and their production of IFN. This is a known maturation stimulus for mDCs and in this way, these cells might even contribute
to sensitization upon viral infections. Activation of epithelial cells by proteolytic allergens, virus infection, TLR ligands, or air pollutants is an indirect way of
activating and polarizing the DC network, through release of thymic stromal lymphopoeitin (TSLP) or granulocyte-macrophage colony stimulating factor
(GM-CSF) or interleukin 1 (IL-1). The precise source and role of endogenous danger signals such as ATP, tumor necrosis factor (TNF-), high mobility group
box 1 (HMGB1), or uric acid is currently being investigated.

and eosinophils (through release of leukotrienes and eosi- pDCs or whether its eects are mediated indirectly through
nophil-specic enzymes) also inuence DC function [34]. modication of any of the above interactions. For systemically
The conditions regulating ATP release in the lungs will have administered TLR agonists, like endotoxin, the activation
to be studied more carefully before we can conclude how of DCs occurs mainly through direct recognition by TLR4
important the pathway of purinergic signaling is in sensiti- expressed on the DC, but in epithelia, the response could be
zation to more common allergens, like house-dust mite. clearly dierent [35]. As an example, low dose endotoxin was
able to break inhalation tolerance to inhaled OVA by induc-
ing mDC maturation [23]. These eects could be mediated
Direct or indirect mechanisms of Th2 directly via TLR and Myd88-dependent pathways in DCs
sensitization to inhaled antigen but could also be mediated via TLRs on bronchial epithelial
cells [36]. Bronchial epithelial cells could produce chemok-
Induction of tolerance or immunity to inhaled antigen by DCs ines as well as crucial growth and dierentiation factors that
is tightly controlled by signals from alveolar macrophages, subsequently attract, activate, and polarize lung DCs to prime
Tregs, NKT cells, complement activation, nervous system Th2 responses. In this regard, the epithelial cytokines thymic
interactions, and epithelial activation. While studying the stromal lymphopoeitin (TSLP) and GM-CSF might be cru-
literature on particular substances that can break inhala- cial, as their overexpression in the lungs breaks inhalational
tion tolerance and induce Th2 priming, one needs to won- tolerance [37, 38]. On the contrary, neutralization of these
der, therefore, whether a stimulus acts directly on mDCs or cytokines, during priming regimens, eliminates much of the

124
Dendritic Cells in Asthma and COPD 10
adjuvant eects of diesel exhaust particles (DEP) [39, 40] or are given [50]. Increased levels of class A scavenger receptors
pro-allergic eects of house-dust mite [41]. Importantly, the (MARCO and SR-AI/II) were found in the lungs of asth-
production of these cytokines by bronchial epithelial cells in matic mice, possibly suppressing DC-driven inammation.
response to these triggers might be genetically regulated and These receptors are expressed on lung macrophages, DCs, and
this could be the explanation why some individuals become basophils. Receptor-decient mice had more eosinophilic air-
primed to inhaled antigen under the right environmental way inammation, airway hyperresponsiveness (AHR), and
exposure [42]. Under some conditions, predictions about sen- increased migration of DCs to the MLN [52].
sitizers or adjuvants can be made from in vitro experiments. The role of mDCs in the secondary immune response
Ambient particulate matter (APM) is ubiquitous in the envi- was further supported by the fact that their depletion at
ronment and is associated with allergic diseases in inner cities. the time of allergen challenge abrogated all the features of
In vitro, inhaled APM can act directly on human DCs as a asthma, including airway inammation, goblet cell hyperpla-
danger signal to direct a proallergic pattern of innate immune sia, and BHR [9]. Again the defect was restored by intrat-
activation, thus explaining why it acts as an adjuvant [43]. racheal injection of GM-CSF cultured CD11bCD11c
Likewise, DEP induce maturation of human DCs indirectly, mDCs, most closely resembling monocyte-derived inam-
via promoting GM-CSF production in bronchial epithelial matory DCs. The same eects were observed when DCs
cells in vitro [40]. In mice, DEP and APM induce altered were depleted in the nose in an animal model for allergic
DC maturation directly, via nuclear factor-erythroid 2 (NF- rhinitis [53]. It therefore seems that inammatory DCs
E2)-related factor 2-mediated signaling, implicating oxidative are both necessary and sucient for secondary immune
stress in the activation of DCs [44]. Whether enhancement responses to allergen. Upon allergen challenge, lung
of inammation in Nrf-2-decient mice, which are hyper- DCs upregulate the expression of CD40, CD80, CD86,
sensitive to oxidative stress, is also the result of overzealous ICOS-L, PD-L1, and PD-L2, particularly upon contact
DC activation remains to be shown [45]. Another known with Th2 cells [9, 11, 48, 49, 54]. Costimulatory molecules
sensitizer is cigarette smoke. When given concomitantly with might be involved in activation of eector T-cells in the tis-
harmless OVA, it induces Th2 responses, and this response sues or in regulation of Treg activity. In allergen-challenged
is associated with enhanced DC maturation and migration mice, DCs might also be a prominent source of the inam-
[46]. DCs developed in a nicotinic environment (nicDCs) matory chemokines CCL17 and CCL22, involved in
fail to support the terminal development of eector memory attracting CCR4 Th2 cells to the airways, and in produc-
Th1 cells due to their dierential expression of costimulatory ing eosinophil-selective chemokines [29, 49]. In helminth
molecules and lack of IL-12 production. In both human and infections, recruitment of Th2 cells and eosinophils depends
mouse, nicDCs promoted the development of Th2 responses on an IL4/IL13-responsive bone marrow-derived cell, most
[47]. As maternal cigarette smoking is a solid risk factor for likely a DC or alternatively an activated macrophage pop-
becoming sensitized in early life, it will be important to eluci- ulation [55]. A number of cytokines and innate immune
date how it leads to DC activation (e.g. whether any indirect response elements control the production of these chemok-
mechanisms acting via epithelial TLR4 contribute), as this ines. The pro-allergic cytokine TSLP induces the production
might provide novel intervention strategies. Another unsolved of large amounts of CCL17 by mDCs, thus contributing to
question is how the nearby nervous endings react to viruses the recruitment of Th2 cells to the airways, explaining how
or air pollution and how this could aect the way DCs react it may act to enhance inammation [37]. The complement
to inhaled allergen. In this regard, the remodeling that occurs factor C5a suppresses the production of CCL17 and
in the airway unmyelinated nerves following RSV virus could CCL22 [29]. A similar eect was seen with the cytokine
partly explain the subsequent enhanced risk of Th2 sensitiza- IL-17, explaining how it may suppress allergic inamma-
tion in mice. tion when given during allergen challenge. In vitro, IL-17
reduced CCL17 production and antigen uptake by DCs and
IL-5 and IL-13 production in regional lymph nodes in vivo.
Furthermore, IL-17 is regulated in an IL-4-dependent man-
Function of DCs in allergic inflammation ner as mice decient for IL-4R signaling showed a marked
and tissue remodeling increase in IL-17 concentration with inhibited eosinophil
recruitment [56]. Emerging evidence suggests that IL4R
Not only do DCs play a role in the primary immune response expression on lung DCs is an important feedback mecha-
to inhaled allergens, they are also crucial during the eector nism through which IL-4 producing cells (eector Th2 cells,
phase of asthma. The number of CD11b DCs is increased in eosinophils, basophils) might promote further Th2 polariza-
the conducting airways and lung interstitium of sensitized and tion in ongoing responses [57].
challenged mice during the acute phase of the response [9, As the number and activation status of lung CD11b
48, 49]. However, during the chronic phase of the pulmonary DCs during the secondary challenge seems critical for con-
response, induced by prolonged exposure to a large number trolling allergic inammation, studying the factors that
of aerosols, respiratory tolerance develops through unclear control recruitment, survival, or egress from the lung dur-
mechanisms. During this regulatory phase, the number of ing allergic inammation will be important, as this might
mDCs as well as their costimulatory molecules in the lungs reveal therapeutic targets. In an elegant study using mixed
steadily decreased, and this was associated with a reduction bone marrow chimeras in which half the hematopoietic
of bronchial hyperresponsiveness (BHR), possibly mediated cells were CCR2/ and half were CCR2/, it was shown
by the action of Treg cells [19, 50, 51]. Inammation how- by Robays et al. that CCR2 (and not CCR5 or CCR6) is
ever reappears when mature inammatory CD11b DCs crucial for releasing DC precursors from the bone marrow

125
Asthma and COPD: Basic Mechanisms and Clinical Management

and attracting them into allergically inamed lung. This cigarette smoke and by activated cells of the innate immune
was unexpected, as CCR6 is generally seen as the chemok- system, causing tissue damage), disturbance in the protease
ine receptor attracting immature DCs into peripheral tis- antiprotease balance (with an elevated production of proteases
sues [58]. Lung mDCs use CCR7 ligands and CCR8 for and/or decreased levels of antiproteases such as 1-anti-
emigration to the draining lymph nodes but not the leuko- trypsin and tissue inhibitors of matrixmetalloprotenases
triene C4 transporter multidrug-related protein-1 as they (TIMP)), increased programmed cell death and probrotic con-
do in the skin [59]. Unexpectedly, disruption of CCR7- ditions in the small airways. The exact pathogenetic mecha-
selective chemokines in paucity of lymphocyte T-cell (plt) nisms for ongoing pulmonary inammation and damage in
mutant mice, decient in CCL21 and CCL19, resulted in COPD, even after the initial inciting agent has disappeared
airway inammation and Th2 activity that were enhanced (i.e. after smoking cessation), are poorly understood. Latent
[60]. Still, increased numbers of mDCs could be found in viral respiratory infections, chronic bacterial colonization of
the draining lymph nodes of these mice. So, in addition to the lower airways, repetitive infectious exacerbations, auto-
CCR7 ligands, there are other factors involved in the migra- immune responses against changed epitopes in the lung,
tion of DCs to the draining LN, including other chemokine and genetic predisposition, are proposed as important driv-
receptors [59]. Eicosanoid lipid mediators like prostaglan- ing mechanisms for the persistent inammation in patients
dins and leukotrienes can also inuence the migration of with COPD [72].
lung DCs [61]. Leukotriene LTB4 promoted the migration The DCs present in the human lung and lymphoid
of immature and mature skin DCs but these eects seem to organs, linking innate and adaptive immune responses,
be indirect [62]. It will be important to study if well-known could be a key element in the pathogenesis of COPD. In the
inducers of LTB4 in the lungs, such as the environmen- remaining part of the chapter, we will discuss what is known
tal biopolymer chitin, derived from fungi, helminthes, and about the eects of cigarette smoke on DCs and how DC
insects, also induce DC migration [63]. Additional drugga- populations are altered in healthy smokers (without airway
ble factors promoting the migration of DCs to the drain- obstruction) and patients with COPD. We will also formu-
ing mediastinal nodes during inammatory responses could late several hypotheses about the role of DC in the patho-
be sphingosine-1-P and extracellular ATP [32, 64]. genesis of COPD.
In humans, allergen challenge leads to an accumula-
tion of myeloid, but not plasmacytoid DCs in the airways
of asthmatics, concomitant with a reduction in circulating DC populations in lungs of smokers and
CD11c cells, showing that these cells are recruited from COPD patients
the bloodstream in response to allergen challenge [65, 66]. A
recent report suggests that pDCs are also recruited into the There have been only a few studies addressing the number
bronchoalveolar lavage (BAL) uid but are poor antigen- and distribution of DCs in the lungs of smokers and
presenting cells (APCs) [66]. The exact role of plasmacytoid patients with COPD. Most of these descriptive studies have
DCs in ongoing allergen-specic responses in asthma is a cross-sectional design, so that the sequence of events can-
currently unknown. It was shown that pDCs accumulate in not be established and any evidence for causality is (very)
the nose, but not lungs, of allergen challenged atopics [67]. weak. At rst sight, some data in the literature appear dis-
When pDCs were pulsed with pollen allergens, they were as crepant or even contradictory, but this may be due to dif-
ecient as mDCs in inducing Th2 proliferation and eec- ferences in the area of interest (bronchial biopsies sampling
tor function [68]. Others have suggested, as in the mouse, large airways versus surgical resection specimens sampling
that pDCs might also confer protection against allergic small airways and parenchyma versus BAL sampling the
responses [16]. In children at high risk of developing atopic alveolar lumen) (Fig. 10.3), dierences in the examination
disease, the number of circulating pDCs was reduced. techniques (electron microscopy, owcytometry, or immu-
nohistochemistry) or dierences in the immunohistochemi-
cal markers used to identify and enumerate the DCs. It is
also critical to discriminate between the eects of smoking
ROLE OF DCS IN COPD per se on DC numbers, phenotypic markers, or functions
versus the disease-specic eects of COPD on DC, irre-
spective of the current smoking status (see Fig. 10.3).
The inflmmatory basis of COPD When studying pulmonary DC, it is important to take
into account not only the dierent DC subsets mentioned
COPD is an inammatory disease of the large and small earlier but also the dierent anatomic locations (i.e. distribu-
airways and the lung parenchyma, which is caused most tion) of DC within the lung. Moreover, the dierent com-
commonly due to the inhalation of noxious particles and partments of the lungs (large airways, small airways, lung
gases and is associated with an abnormal systemic inam- parenchyma interstitium and alveolar lumen) are sampled
matory response. The lungs of COPD patients are inltrated by dierent methods (bronchoscopy, surgical lung resec-
with cells of the innate immune system such as neutrophils tions, and BAL, respectively). In the large airways (trachea,
and macrophages [69], but there is also evidence for an bronchi), sampled by bronchoscopy with bronchial biopsies,
activated adaptive immune response with accumulation of the number of CD1a DC was evaluated in healthy smok-
CD8 T-cells, Bcells, and the presence of lymphoid fol- ing controls and current smoking COPD patients, showing
licles [70, 71]. Four key elements appear to be crucial in the no signicant dierences between groups [73, 74]. Others
pathogenesis of COPD: increased oxidative stress (caused by evaluated the number of DC in large airways using electron

126
Dendritic Cells in Asthma and COPD 10
never-smokers and healthy-smokers (without COPD), sug-
Cigarette smoke COPD gesting an accumulation of Langerhans-type DC in COPD
[77]. Moreover, the number of Langerin DC further
increased with the severity of the disease [77].
EM defined DC CD1a DC Studies sampling BAL uid evaluated the number of
(Rogers et al., 2008) (Verhoeven et al., 2002)
DCs between never-smokers and smokers without COPD,
Large showing a signicant increase in the expression of Langerin
airway
and CD1a (markers of Langerhans cells) on myeloid DC
[78] as well as an increase in Birbeck granule positive
Langerhans-type DC in smokers versus non-smokers [79].
Finally, in the alveolar parenchyma, the number of CD1a
DC was increased in smokers versus never-smokers, whereas
the number of CD1c DC was not dierent [76].
Taken together, evidence points toward an accumulation
of myeloid DC with Langerhans-type cell markers (CD207,
CD1a, and Birbeck granules) in the small airways and alveoli
of smokers and COPD patients. This is in agreement with
CD1a DC Small data from experimental models of COPD, in which mice are
CD1c DC airway Langerin DC chronically exposed to cigarette smoke and develop manifest
(Soler et al., 1989) (Demedts et al., 2007)
pulmonary inammation and emphysema. A clear accumula-
Langerin DC tion of myeloid DC was seen in the BAL uid and lungs of
CD1a DC these mice [80], exposed to relatively high doses of cigarette
CD1c DC smoke (with carboxyhemoglobin levels in serum compara-
Alveolus
(Bratke et al., 2008) ble to the levels obtained in human smokers who smoke 20
Birbeck DC cigarettes a day). However, exposing the mice to a lower dose
(Casolaro et al., 1988)
of cigarette smoke appears to decrease the number of DCs in
CD1a DC the lung in the absence of inammation [81].
CD1c DC Interstitium
(Soler et al., 1989)

FIG. 10.3 Distribution of DCs in the lungs and the impact of smoking or
Functional differences in DCs exposed to
COPD on different subsets of dendritic cells. Myeloid DCs can be retrieved cigarette smoke
in different compartments of the lung. Airway DCs are located as a network
immediately above and beneath the basement membrane, either in the Evidence from the mouse model of COPD and from
large airways (sampled by bronchial biopsies taken during bronchoscopy) human lung tissue suggests an activated macrophage
or in the small airways (present in lung resection specimens). Alveolar inammatory protein 3 (MIP3alpha)/CC-chemokine
DCs are present in the lumen of alveolar spaces and can be recovered by
ligand (CCL20)CC-chemokine receptor 6 (CCR6)-axis in
BAL, whereas interstitial DCs are located in the interstitium of the lung
parenchyma between alveolar spaces (also present in lung resection
COPD, responsible for the accumulation of myeloid DC in
specimens). The exact location of human plasmacytoid DCs has still to be the lung [77, 82]. At the epithelial surface, DCs are capable
elucidated. On the left side of the figure, studies evaluating the impact of sensing danger signals and take up antigens to process
of cigarette smoking per se on the number of different myeloid DCs are them. However, little is known about the inuence of ciga-
indicated and summarized; on the right side, the studies comparing the rette smoke on the expression and function of innate recep-
number of CD1a DC (in large airways) or Langerin DCs (in small airways) tors of DCs, including TLR and lectin-like receptors (such
between patients with COPD and healthy-smokers without airflow as Langerin and blood DC antigen-2 [83]). Once the DC
limitation are indicated. COPD: chronic obstructive pulmonary disease; has sampled the antigen, it will process the a