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Murray & Nadel’s
Textbook of
Respiratory Medicine
SEVENTH EDITION

Editor-in-Chief Lynn M. Schnapp, MD

V. Courtney Broaddus, MD George R. and Elaine Love Professor
Professor Emeritus of Medicine Chair, Department of Medicine
University of California San Francisco School of Medicine and Public Health
Division of Pulmonary and Critical Care Medicine University of Wisconsin-Madison
Zuckerberg San Francisco General Hospital Madison, Wisconsin
San Francisco, California Renee D. Stapleton, MD, PhD
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Editors University of Vermont Larner College of Medicine
Joel D. Ernst, MD Burlington, Vermont
Professor of Medicine
Chief, Division of Experimental Medicine
University of California San Francisco School of Medicine Thoracic Imaging Editor
San Francisco, California Michael B. Gotway, MD
Talmadge E. King Jr, MD Professor of Radiology
Dean, UCSF School of Medicine Department of Diagnostic Imaging
Vice Chancellor for Medical Affairs Mayo Clinic
University of California San Francisco Scottsdale, Arizona;
San Francisco, California Clinical Associate Professor
Departments of Diagnostic Radiology and Biomedical
Stephen C. Lazarus, MD, FCCP, FERS Imaging, and Pulmonary and Critical Care Medicine
Professor of Medicine University of California San Francisco
Division of Pulmonary and Critical Care Medicine San Francisco, California;
Senior Investigator, Cardiovascular Research Institute Clinical Professor
University of California San Francisco University of Arizona College of Medicine
San Francisco, California Phoenix, Arizona;
Adjunct Professor
Kathleen F. Sarmiento, MD, MPH Department of Biomedical Informatics
Associate Professor of Medicine
Arizona State University
Division of Pulmonary, Critical Care, and Sleep Medicine
Tempe, Arizona
University of California San Francisco;
San Francisco VA Healthcare System
San Francisco, California
Elsevier
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MURRAY & NADEL’S TEXTBOOK OF RESPIRATORY MEDICINE, ED 7  ISBN: 978-0-323-65587-3

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Previous editions copyrighted © 2016, 2010, 2005 by Saunders, an imprint of Elsevier, Inc.

Cover images courtesy Michael B. Gotway, MD (images 1 and 4), and U.S. Centers for Disease Control and
Prevention/Alissa Eckert, MSMI; Dan Higgins, MAMS (image 2); https://phil.cdc.gov/Details.aspx?pid=23311.

Executive Content Strategist: Robin Carter

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Printed in Canada

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 We dedicate this Textbook to Dr. John F. Murray. In 1988, Dr. Murray, together with Dr. Jay A. Nadel,
published the first edition of this Textbook. Motivated by his love of teaching, he aimed to create a
comprehensive, clear, authoritative, thoroughly annotated compendium of respiratory medicine, always
integrated with scientific principles. Over the subsequent years and six more editions, he inspired us to
continue his work and to maintain his high standards.
Of all his contributions to respiratory medicine, he was perhaps most proud of the Textbook.

John F. Murray, MD
(1927-2020)
Dedication

To my husband, Chuck, who has been the bedrock. For my parents, to whom I owe all I have, and to my
To the rest of our wonderful family, Chris and Clay, Mary loving wife and daughter, Mary Pat and Allison, for all
and Lydia, and the grandboys Charlie and Rory. the support and inspiration they provide.
Michael B. Gotway, MD
To my mentors, colleagues and fellow editors for their
inspiration and support of my career and of this project.
V. Courtney Broaddus, MD

To Vicki, Kristina, and Genevieve, who make everything To my wife, Mozelle D. King
worthwhile. To my children, Consuelo King and Malaika King Kattke
Joel Ernst, MD
To my grandchildren, Madison and Siena Kattke
To the memories of my mother and father, Almetta and
Talmadge King
Talmadge E. King Jr, MD

To my wife, Gail, who makes everything possible, and
better; to my daughter, Hillary, and her husband,
Andrew, who continue to ask about what I do, and
encourage it; to my grandchildren Lola and Axel, who
give me hope for the future and joy in the present; and
to the many colleagues, students, and trainees, who
made my first 49 years at UCSF so enjoyable.
Stephen C. Lazarus, MD, FCCP, FERS
To my parents, Barbara and Barry Brennan, who taught
by example the value of hard work, perseverance,
and compassion.
Kathleen F. Sarmiento, MD, MPH
Dedication vii
In loving memory of my parents, who were
an ­unwavering source of support and encouragement
for ­everything that I did. They may not have
understood why I ran, but they were always at the finish
line to cheer me on.
Lynn M. Schnapp, MD
To my husband Jonathan; our children Walker,
­Emmerson, and Orion; my parents Myrna and Ted;
and my mentors, colleagues, patients, and trainees for a
lifetime of pushing me to learn, grow, and change.
Renee D. Stapleton, MD, PhD
Contributors
Lewis Adams, PhD
Professor of Physiology
School of Allied Health Sciences
Griffith University
Gold Coast, Queensland, Australia
Chapter 36: Dyspnea
Rosemary Adamson, MB, BS
Associate Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
University of Washington School of Medicine
Veterans Affairs Puget Sound Healthcare System
Seattle, Washington
Chapter 23: Ultrasonography: Principles and Basic
­Thoracic and Vascular Imaging
Dan E. Adler, MD
Professor of Pulmonary Medicine
Division of Pneumology
University Hospital of Geneva
Geneva, Switzerland
Chapter 136: Noninvasive Support of Ventilation
Evangelia Akoumianaki, MD, PhD
Consultant
Intensive Care Unit
University Hospital of Heraklion
Heraklion, Crete, Greece
Chapter 136: Noninvasive Support of Ventilation
Tyler J. Albert, MD
Assistant Professor of Medicine
Department of Medicine
Division of General Internal Medicine
University of Washington School of Medicine
Veterans Affairs Puget Sound Health Care System
Seattle, Washington
Chapter 12: Acid-­Base Balance
Kurt H. Albertine, PhD, FAAAS, FAAA
Edward B. Clark Endowed Chair IV in Pediatrics
Adjunct Professor of Medicine and Neurobiology and
Anatomy
University of Utah School of Medicine
Editor-­in-­Chief, The Anatomical Record
Salt Lake City, Utah
Chapter 1: Anatomy
Barbara D. Alexander, MD, MHS
Professor of Medicine and Pathology
Division of Infectious Diseases
Duke University Medical Center
Durham, North Carolina
Chapter 57: Fungal Infections: Opportunistic
viii
Christopher I. Amos, PhD
Professor of Medicine
Director, Institute for Clinical and Translational
Research Medicine
Associate Director of Quantitative Science
Dan L. Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas
Chapter 74: Lung Cancer: Epidemiology
Douglas A. Arenberg, MD, FACCP
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of Michigan Medical School
Ann Arbor, Michigan
Chapter 79: Metastatic Malignant Tumors
Chapter 80: Benign Lung Tumors
A. Christine Argento, MD, FCCP
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Northwestern University Feinberg School of Medicine
Chicago, Illinois;
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Johns Hopkins University School of Medicine
Baltimore, Maryland
Chapter 27: Diagnostic Bronchoscopy: Advanced
­Techniques (EBUS and Navigational)
Shaikh M. Atif, PhD
Instructor of Medicine
Division of Clinical Immunology
University of Colorado Anschutz Medical Campus
Aurora, Colorado
Chapter 16: Adaptive Immunity
Najib T. Ayas, MD, MPH
Associate Professor of Medicine
University of British Columbia Faculty of Medicine
Vancouver, British Columbia, Canada
Chapter 11: Respiratory System Mechanics and Energetics
Jennifer M. Babik, MD, PhD
Associate Clinical Professor of Medicine
Division of Infectious Diseases
University of California San Francisco School of Medicine
San Francisco, California
Chapter 46a: COVID-­19
Jessica B. Badlam, MD
Assistant Professor of Medicine
Division of Pulmonary Disease and Critical Care Medicine
University of Vermont Larner College of Medicine
Burlington, Vermont
Chapter 39: Wheezing and Stridor
 Contributors ix

John Randolph Balmes, MD Joshua O. Benditt, MD

Professor of Medicine
Division of Occupational and Environmental Medicine
University of California San Francisco
Division of Pulmonary and Critical Care Medicine
Zuckerberg San Francisco General Hospital
San Francisco, California;
Professor of Environmental Health Sciences
University of California Berkeley School of Public Health
Berkeley, California
Chapter 102: Indoor and Outdoor Air Pollution
Niaz Banaei, MD
Professor
Departments of Pathology and Medicine (Infectious
Diseases)
Stanford University School of Medicine
Stanford, California;
Medical Director, Clinical Microbiology Laboratory
Stanford University Medical Center
Palo Alto, California
Chapter 19: Microbiologic Diagnosis of Lung Infection
Christopher F. Barnett, MD, MPH
Director, Pulmonary Hypertension Program
Director, Medical Cardiovascular Intensive Care Unit
Department of Cardiology
Medstar Washington Hospital Center
Washington, DC
Chapter 24: Ultrasonography: Advanced Applications and
Procedures
Chapter 85: Pulmonary Hypertension Due to Lung
­Disease: Group 3
Sonja D. Bartolome, MD
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of Texas Southwestern Medical Center
Dallas, Texas
Chapter 84: Pulmonary Arterial Hypertension:
Group 1
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of Washington School of Medicine
Director, Respiratory Care Services
University of Washington Medical Center
Seattle, Washington
Chapter 130: The Respiratory System and Neuromuscu-
lar Diseases
Neal L. Benowitz, MD
Emeritus Professor of Medicine
University of California San Francisco;
Attending Physician
Departments of Medicine and Biopharmaceutical Sciences
Program in Clinical Pharmacology
Division of Cardiology
Zuckerberg San Francisco General Hospital
San Francisco, California
Chapter 65: Smoking Hazards: Cigarettes, Vaping, Marijuana
Nirav R. Bhakta, MD, PhD
Associate Professor of Medicine
Division of Pulmonary, Critical Care, Allergy, and Sleep
Medicine
Director of Education and Associate Director, Adult Pulmo-
nary Function Laboratory
University of California San Francisco
San Francisco, California
Chapter 31: Pulmonary Function Testing: Physiologic
and Technical Principles
Chapter 32: Pulmonary Function Testing: Interpretation
and Applications
Chapter 60: Asthma: Pathogenesis and Phenotypes
Rahul Bhatnagar, MBChB, PhD
Honorary Lecturer
Academic Respiratory Unit
University of Bristol
Bristol, United Kingdom
Chapter 112: Pleural Fibrosis and Unexpandable Lung

Robert P. Baughman, MD Surya P. Bhatt, MD, MSPH

Professor of Medicine Associate Professor of Medicine
Department of Internal Medicine Division of Pulmonary, Allergy, and Critical Care Medicine
University of Cincinnati College of Medicine Medical Director, Pulmonary Function and Exercise
Cincinnati, Ohio Physiology Laboratory
Chapter 93: Sarcoidosis University of Alabama at Birmingham
Birmingham, Alabama
Michael F. Beers, MD Chapter 32: Pulmonary Function Testing: Interpretation
Robert L. Mayock and David A. Cooper Professor of and Applications
Medicine
Department of Medicine Anna C. Bibby, MBChB, BSC, MRCP
Division of Pulmonary and Critical Care Academic Respiratory Unit
Perelman School of Medicine at the University of Translational Health Sciences
Pennsylvania University of Bristol Medical School;
Philadelphia, Pennsylvania Respiratory Department
Chapter 3: Alveolar Compartment North Bristol NHS Trust
Bristol, United Kingdom
Chapter 109: Pleural Infections
x Contributors

Alexandra Binnie, MD, DPhil, FRCP(C) Steven L. Brody, MD

Invited Assistant Professor Dorothy R. and Hubert C. Moog Professor of Pulmonary
University of Algarve Medicine
Faro, Portugal; Washington University School of Medicine in St. Louis
Critical Care Physician St. Louis, Missouri
William Osler Health System Chapter 4: Airway Biology
Toronto, Canada
Chapter 134: Acute Respiratory Distress Syndrome Kevin K. Brown, MD
Professor and Chair
Paul D. Blanc, MD, MSPH Department of Medicine
Professor of Medicine National Jewish Health
Endowed Chair in Occupational and Environmental Denver, Colorado;
Medicine Professor of Medicine
University of California San Francisco Division of Pulmonary Sciences and Critical Care Medicine
Chief, Division of Occupational and Environmental University of Colorado School of Medicine
Medicine Aurora, Colorado
UCSF Medical Center Chapter 87: Pulmonary Vasculitis
San Francisco, California
Chapter 103: Acute Responses to Toxic Exposures Paul G. Brunetta, MD
Adjunct Associate Professor of Medicine
Zea Borok, MB, ChB Division of Pulmonary and Critical Care Medicine
Professor of Medicine and Biochemistry and Molecular University of California San Francisco;
Medicine Fontana Tobacco Treatment Center
Division of Pulmonary, Critical Care, and Sleep Medicine Mt. Zion Medical Center
Keck School of Medicine San Francisco, California
University of Southern California Chapter 66: Smoking Cessation
Los Angeles, California
Chapter 3: Alveolar Compartment Jacques Cadranel, MD, PhD
Professor of Respiratory Medicine
T. Douglas Bradley, MD, FRCPC Service de Pneumologie
Professor of Medicine Hôpital Tenon, Assistance Publique Hôpitaux de Paris
Director, Division of Respirology Paris, France
Centre for Sleep Medicine and Circadian Biology Chapter 78: Rare Primary Lung Tumors
University of Toronto Faculty of Medicine;
Director, Sleep Medicine Laboratory Shamus R. Carr, MD
University Health Network Associate Research Physician
Toronto Rehabilitation Institute Thoracic Surgery Branch
Toronto General Hospital Center for Cancer Research
Toronto, Ontario, Canada National Cancer Institute
Chapter 121: Central Sleep Apnea Bethesda, Maryland
Chapter 30: Thoracic Surgery
V. Courtney Broaddus, MD
Professor Emeritus of Medicine Tara F. Carr, MD
University of California San Francisco Associate Professor of Medicine
Division of Pulmonary and Critical Care Medicine College of Medicine, Tucson
Zuckerberg San Francisco General Hospital Asthma and Airway Disease Research Center
San Francisco, California University of Arizona Health Sciences
Chapter 14: Pleural Physiology and Pathophysiology Tucson, Arizona
Chapter 44: Hypoxemia Chapter 62: Asthma: Diagnosis and Management
Chapter 108: Pleural Effusion
Adithya Cattamanchi, MD, MAS
Laurent J. Brochard, MD Professor of Medicine and Epidemiology
Interdepartmental Division Director for Critical Care Division of Pulmonary and Critical Care Medicine
University of Toronto Faculty of Medicine University of California San Francisco Center for
Full Professor and Clinician Scientist Tuberculosis
Department of Medicine University of California San Francisco School of Medicine
Division of Critical Care San Francisco, California
Saint Michael’s Hospital Chapter 53: Tuberculosis: Clinical Manifestations and
Keenan Research Center for Biomedical Science Diagnosis
Toronto, Ontario, Canada
Chapter 136: Noninvasive Support of Ventilation
 Contributors xi

Lara Chalabreysse, MD Michael H. Cho, MD, MPH

Département de Pathologie Associate Professor of Medicine
Groupement Hospitalier Est Hospices Civils de Lyon Channing Division of Network Medicine and Division of
Lyon, France Pulmonary and Critical Care Medicine
Chapter 78: Rare Primary Lung Tumors Brigham and Women’s Hospital
Harvard Medical School
Edward D. Chan, MD Boston, Massachusetts
Professor of Medicine Chapter 9: Genetics of Lung Disease
University of Colorado Anschutz Medical Campus Chapter 63: COPD: Pathogenesis and Natural History
Staff Physician
Department of Medicine David C. Christiani, MD
Rocky Mountain Regional Veterans Affairs Medical Center Professor of Medicine
Aurora, Colorado; Harvard Medical School
Staff Physician Elkan Blout Professor of Environmental Genetics
Department of Academic Affairs Department of Environmental Health
National Jewish Health Harvard School of Public Health;
Denver, Colorado Physician
Chapter 69: Bronchiectasis Division of Pulmonary and Critical Care
Massachusetts General Hospital
Ken K.P. Chan, MBChB, MRCP (UK), FHKCP, FHKAM Boston, Massachusetts
Clinical Assistant Professor (Honorary) Chapter 74: Lung Cancer: Epidemiology
Department of Medicine & Therapeutics
Chinese University of Hong Kong; Kian Fan Chung, MD, DSc, FRCP
Associate Consultant Professor of Respiratory Medicine
Department of Medicine & Therapeutics Head of Experimental Studies
Prince of Wales Hospital National Heart & Lung Institute
Hong Kong Imperial College London;
Chapter 111: Chylothorax Consultant Physician
Royal Brompton and Harefield NHS Trust
Jean Chastre, MD London, United Kingdom
Professor Chapter 37: Cough
Service de Réanimation Médicale
Institut de Cardiologie, Groupe Hospitalier Pitié-­Salpêtrière Amelia O. Clive, MBBS, PhD
Paris, France Consultant in Thoracic Medicine
Chapter 49: Ventilator-­Associated Pneumonia North Bristol Lung Centre
Southmead Hospital
Guang-­Shing Cheng, MD Bristol, United Kingdom
Associate Professor, Clinical Research Division Chapter 112: Pleural Fibrosis and Unexpandable Lung
Fred Hutchinson Cancer Research Center;
Associate Professor of Medicine Robert A. Cohen, MD
Division of Pulmonary, Critical Care, and Sleep Medicine Professor of Medicine
University of Washington School of Medicine Northwestern University Feinberg School of Medicine
Seattle, Washington Clinical Professor of Environmental and Occupational
Chapter 115: Mediastinal Tumors and Cysts Health Sciences
Chapter 125: Pulmonary Complications of Stem Cell and University of Illinois at Chicago School of Public Health
Solid Organ Transplantation Chicago, Illinois
Chapter 101: Pneumoconioses
Kelly M. Chin, MD, MSCS
Associate Professor of Medicine Thomas V. Colby, MD
Division of Pulmonary and Critical Care Medicine Professor Emeritus
Director, Pulmonary Hypertension Program Department of Laboratory Medicine and Pathology
University of Texas Southwestern Medical Center Mayo Clinic Alix College of Medicine
Dallas, Texas Scottsdale, Arizona
Chapter 84: Pulmonary Arterial Hypertension: Group 1 Chapter 89: Idiopathic Pulmonary Fibrosis
xii Contributors

Carlyne D. Cool, MD Charles L. Daley, MD

Clinical Professor of Pathology
University of Colorado School of Medicine
Aurora, Colorado;
Adjunct Professor
National Jewish Health
Denver, Colorado
Chapter 87: Pulmonary Vasculitis
Ricardo Luiz Cordioli, MD, PhD
Medical Staff
Division of Intensive Care
Albert Einstein Hospital
Oswaldo Cruz Hospital
São Paulo, Brazil;
Intensive Care Unit
University Hospital of Geneva
Geneva, Switzerland
Chapter 136: Noninvasive Support of Ventilation
Tamera J. Corte, MBBS, PhD, FRACP
Associate Professor of Medicine
University of Sydney Medical School
Consultant Respiratory Physician
Director of Interstitial Lung Disease Service
Royal Prince Alfred Hospital
Sydney, Australia
Chapter 92: Connective Tissue Diseases
Vincent Cottin, MD, PhD
Professor of Respiratory Medicine
Claude Bernard University
University of Lyon;
Head, Coordinating Reference Center for Rare Pulmonary
Diseases, Hospices Civils de Lyon
Louis Pradel Hospital
Lyon, France
Chapter 96: Eosinophilic Lung Diseases
Kristina Crothers, MD
Professor of Medicine
University of Washington School of Medicine
Chief, Section of Pulmonary, Critical Care, and Sleep
Medicine
Veterans Affairs Puget Sound Health Care System
Seattle, Washington
Chapter 123: Pulmonary Complications of HIV Infection
Jeffrey L. Curtis, MD
Professor of Internal Medicine
University of Michigan Medical School
Staff Physician, Medicine Service
VA Ann Arbor Healthcare System
Ann Arbor, Michigan
Chapter 63: COPD: Pathogenesis and Natural History
Professor and Chief
Division of Mycobacterial and Respiratory Infections
National Jewish Health
Denver, Colorado;
Professor of Medicine
Division of Pulmonary and Critical Care Medicine and
Infectious Diseases
University of Colorado School of Medicine
Aurora, Colorado;
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Icahn School of Medicine at Mt Sinai
New York, New York
Chapter 55: Nontuberculous Mycobacterial Infections
Bruce L. Davidson, MD, MPH
Former Clinical Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of Washington School of Medicine
Seattle, Washington
Chapter 82: Pulmonary Thromboembolism: Prophylaxis
and Treatment
Helen E. Davies, MD, FRCP
Consultant Respiratory Physician
Department of Respiratory Medicine
University Hospital of Wales
Cardiff, United Kingdom
Chapter 114: Pleural Malignancy
J. Lucian Davis, MD
Associate Professor of Epidemiology
Department of Epidemiology of Microbial Diseases
Yale School of Public Health;
Associate Professor of Medicine
Pulmonary, Critical Care, and Sleep Medicine Section
Yale School of Medicine
New Haven, Connecticut
Chapter 18: History and Physical Examination
Teresa De Marco, MD
Professor of Medicine
RH and Jane G. Logan Endowed Chair in Cardiology
Chief, Advanced Heart Failure and Pulmonary
Hypertension
Medical Director, Heart Transplantation
University of California San Francisco
San Francisco, California
Chapter 85: Pulmonary Hypertension Due to Lung
­Disease: Group 3
Stanley C. Deresinski, MD
Clinical Professor of Medicine
Division of Infectious Diseases and Geographic Medicine
Stanford University School of Medicine
Stanford, California
Chapter 19: Microbiologic Diagnosis of Lung Infection
 Contributors xiii

Christophe M. Deroose, MD, PhD C. Gregory Elliott, MD

Associate Professor of Nuclear Medicine and Molecular Professor of Internal Medicine
Imaging University of Utah School of Medicine
Katholieke Universiteit Leuven; Salt Lake City, Utah;
Deputy Head of Clinic Chairman, Department of Medicine
Nuclear Medicine Intermountain Medical Center
University Hospitals Leuven Murray, Utah
Leuven, Belgium Chapter 82: Pulmonary Thromboembolism: Prophylaxis
Chapter 25: Positron Emission Tomography and Treatment

Anne E. Dixon, MA, BM, BCh Joel D. Ernst, MD

Professor of Medicine Professor of Medicine
Chief, Division of Pulmonary Disease and Critical Care Chief, Division of Experimental Medicine
Medicine University of California San Francisco School of Medicine
Director, Vermont Lung Center San Francisco, California
University of Vermont Larner College of Medicine Chapter 52: Tuberculosis: Pathogenesis and Immunity
Burlington, Vermont
Chapter 61: Asthma and Obesity Christopher M. Evans, PhD
Professor of Medicine
David H. Dockrell, MD, FRCPI, FRCP(Glas), FACP Division of Pulmonary Sciences and Critical Care
Professor of Infection Medicine University of Colorado School of Medicine
University of Edinburgh Aurora, Colorado
Edinburgh, United Kingdom Chapter 4: Airway Biology
Chapter 46: Community-­Acquired Pneumonia
John V. Fahy, MD, MSc
Christophe Dooms, MD, PhD Professor of Medicine
Assistant Professor of Pneumology Division of Pulmonary, Critical Care, Allergy, and Sleep
Katholieke Universiteit Leuven; Medicine
Deputy Head of Clinic Cardiovascular Research Institute
Pneumonology University of California San Francisco
University Hospitals Leuven San Francisco, California
Leuven, Belgium Chapter 60: Asthma: Pathogenesis and Phenotypes
Chapter 25: Positron Emission Tomography
Elaine Fajardo, MD
Gregory P. Downey, MD Assistant Professor of Medicine
Executive Vice President, Academic Affairs Pulmonary, Critical Care, and Sleep Medicine Section
Department of Medicine Yale School of Medicine
National Jewish Health; New Haven, Connecticut
Professor Chapter 18: History and Physical Examination
Departments of Medicine and Immunology and
Microbiology Eddy Fan, MD, PhD
Associate Dean Associate Professor of Medicine
University of Colorado Denver School of Medicine Interdepartmental Division of Critical Care Medicine
Denver, Colorado University of Toronto Faculty of Medicine
Chapter 8: Regeneration and Repair Toronto, Ontario, Canada
Chapter 135: Mechanical Ventilation
Hilary DuBrock, MD, MMSc
Assistant Professor of Medicine Marie E. Faughnan, MD, MSc
Mayo Clinic Professor of Medicine
Rochester, Minnesota Division of Respirology
Chapter 126: Pulmonary Complications of Abdominal University of Toronto Faculty of Medicine
Diseases Toronto, Ontario, Canada
Chapter 88: Pulmonary Vascular Anomalies
Souheil El-­Chemaly, MD, MPH
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Chapter 7: Lymphatic Biology
xiv Contributors

David Feller-­Kopman, MD, FCCP Stephen K. Frankel, MD, FCCM, FCCP

Professor of Medicine, Anesthesiology, and Otolaryngology– Executive Vice President, Clinical Affairs
Head and Neck Surgery Professor of Medicine
Director, Bronchoscopy and Interventional Pulmonology National Jewish Health
Department of Pulmonary and Critical Care Medicine Denver, Colorado;
Johns Hopkins Medical Institutions Professor of Medicine
Baltimore, Maryland Division of Pulmonary Sciences and Critical Care Medicine
Chapter 27: Diagnostic Bronchoscopy: Advanced University of Colorado School of Medicine
­Techniques (EBUS and Navigational) Aurora, Colorado
Chapter 28: Therapeutic Bronchoscopy: Interventional Chapter 87: Pulmonary Vasculitis
­Techniques
Joseph Friedberg, MD
Brett E. Fenster, MD Charles Reid Edwards Professor of Surgery
Cardiologist Head, Division of Thoracic Surgery
Kaiser Permanente Director, Pleural Mesothelioma Program
Denver, Colorado University of Maryland School of Medicine
Chapter 38: Chest Pain Baltimore, Maryland
Chapter 30: Thoracic Surgery
Timothy M. Fernandes, MD, MPH Chapter 113: Hemothorax
Associate Clinical Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine Monica Fung, MD
University of California San Diego School of Medicine Assistant Professor of Medicine
San Diego, California Division of Infectious Diseases
Chapter 86: Pulmonary Hypertension Due to Chronic University of California San Francisco School of Medicine
­Thromboembolic Disease: Group 4 San Francisco, California
Chapter 46a: COVID-­19
Evans R. Fernández Pérez, MD, MS
Associate Professor of Medicine Yuansheng Gao, PhD
Division of Pulmonary, Critical Care, and Sleep Medicine Professor of Physiology and Pathophysiology
National Jewish Health Peking University Health Science Center
Denver, Colorado Beijing, China
Chapter 91: Hypersensitivity Pneumonitis Chapter 6: Vascular Biology

William A. Fischer II, MD Erik Garpestad, MD

Assistant Professor of Medicine Associate Professor of Medicine
Institute of Global Health and Infectious Diseases Division of Pulmonary, Critical Care, and Sleep Medicine
Division of Pulmonary and Critical Care Medicine Director, Medical ICU
The University of North Carolina School of Medicine Tufts Medical Center
Chapel Hill, North Carolina Boston, Massachusetts
Chapter 59: Outbreaks, Pandemics, and Bioterrorism Chapter 132: Acute Ventilatory Failure

Andrew P. Fontenot, MD Eric J. Gartman, MD

Henry N. Claman Professor of Medicine Associate Professor of Medicine
Division of Clinical Immunology Division of Pulmonary, Critical Care, and Sleep Medicine
University of Colorado Anschutz Medical Campus Alpert Medical School of Brown University;
Aurora, Colorado Staff Physician
Chapter 16: Adaptive Immunity Division of Pulmonary, Critical Care, and Sleep Medicine
Providence VA Medical Center
Providence, Rhode Island
James Frank, MD, MA
Chapter 131: The Respiratory System and Chest Wall
Professor of Clinical Medicine
Division of Pulmonary, Critical Care, Allergy, and Sleep Diseases
Medicine
University of California San Francisco School of Medicine G.F. Gebhart, PhD
San Francisco, California Professor of Anesthesiology, Medicine, Neurobiology, and
Chapter 23: Ultrasonography: Principles and Basic Pharmacology
­Thoracic and Vascular Imaging Director, Center for Pain Research
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Chapter 38: Chest Pain
 Contributors xv

Gautam George, MD Robb W. Glenny, MD

Assistant Professor of Medicine Professor of Medicine and of Physiology and Biophysics
Division of Pulmonary, Allergy, and Critical Care Medicine Division of Pulmonary and Critical Care Medicine
Jane and Leonard Korman Respiratory Institute University of Washington School of Medicine
Sidney Kimmel Medical College Seattle, Washington
Thomas Jefferson University Chapter 33: Exercise Testing
Philadelphia, Pennsylvania
Chapter 5: Lung Mesenchyme Ewan C. Goligher, MD, PhD
Assistant Professor of Medicine
Yaron B. Gesthalter, MD Interdepartmental Division of Critical Care Medicine
Assistant Professor of Medicine University of Toronto Faculty of Medicine;
Division of Pulmonary and Critical Care Scientist
Section of Interventional Pulmonology Toronto General Hospital Research Institute;
University of California San Francisco School of Medicine Attending Physician
San Francisco, California Department of Medicine, Division of Respirology
Chapter 40: Hemoptysis University Health Network
Toronto, Ontario, Canada
Mark T. Gladwin, MD Chapter 135: Mechanical Ventilation
Jack D. Myers Professor and Chair
Department of Medicine Antonio Gomez, MD
University of Pittsburgh School of Medicine Associate Professor of Medicine
Director, Pittsburgh Heart, Lung, Blood, and Vascular University of California San Francisco
Medicine Institute Medical Director, Critical Care Services
University of Pittsburgh Medical Center Zuckerberg San Francisco General Hospital
Pittsburgh, Pennsylvania San Francisco, California
Chapter 127: Pulmonary Complications of Hematologic Chapter 44: Hypoxemia
Diseases
Anne V. Gonzalez, MD, MSc
Leonard H.T. Go, MD Associate Professor of Medicine
McGill University Faculty of Medicine
Research Assistant Professor of Environmental and
Montreal, Quebec, Canada
­Occupational Health Sciences
University of Illinois at Chicago School of Public Health; Chapter 76: Lung Cancer: Diagnosis and Staging
Department of Medicine
Stroger Hospital of Cook County; Stephen B. Gordon, MD, MA, FRCP, DTM&H
Department of Medicine Director, Malawi Liverpool Wellcome Programme
Northwestern University Feinberg School of Medicine University of Malawi College of Medicine
Chicago, Illinois Blantyre, Malawi;
Professor of Clinical Sciences
Chapter 101: Pneumoconioses
Liverpool School of Tropical Medicine
Liverpool, United Kingdom
Nisha H. Gidwani, MD Chapter 46: Community-­Acquired Pneumonia
Associate Professor of Clinical Medicine
Division of Pulmonary, Critical Care, Allergy, and Sleep
Dominique Gossot, MD
Medicine Institut du Thorax Curie Montsouris
University of California San Francisco Institut Mutualiste Montsouris
San Francisco, California Paris, France
Chapter 50: Lung Abscess Chapter 78: Rare Primary Lung Tumors
Nicolas Girard, MD, PhD Jeffrey E. Gotts, MD, PhD
Professor of Respiratory Medicine Assistant Professor of Medicine
Institut du Thorax Curie Montsouris Division of Pulmonary and Critical Care Medicine
Institut Curie University of California San Francisco
Paris, France San Francisco, California
Chapter 78: Rare Primary Lung Tumors Chapter 65: Smoking Hazards: Cigarettes, Vaping, Marijuana
xvi Contributors

Michael B. Gotway, MD Nishant Gupta, MD, MS

Professor of Radiology Associate Professor of Internal Medicine
Department of Diagnostic Imaging Division of Pulmonary, Critical Care, and Sleep Medicine
Mayo Clinic University of Cincinnati College of Medicine
Scottsdale, Arizona; Cincinnati, Ohio
Clinical Associate Professor Chapter 97: Lymphangioleiomyomatosis
Departments of Diagnostic Radiology and Biomedical
Imaging, and Pulmonary and Critical Care Medicine Rob Hallifax, DPhil, BMCh, MSc, MRCP
University of California San Francisco Academic Clinical Lecturer
San Francisco, California; Respiratory Trials Unit
Clinical Professor Oxford Centre for Respiratory Medicine
University of Arizona College of Medicine Churchill Hospital NHS Trust
Phoenix, Arizona; Oxford, United Kingdom
Adjunct Professor Chapter 110: Pneumothorax
Department of Biomedical Informatics
Arizona State University
Tempe, Arizona Meilan K. Han, MD, MS
Professor of Medicine
Chapter 20: Thoracic Radiology: Noninvasive Diagnostic Division of Pulmonary and Critical Care Medicine
­Imaging University of Michigan School of Medicine
Ann Arbor, Michigan
Michael Gould, MD, MS Chapter 64: COPD: Diagnosis and Management
Director for Health Services Research
Department of Research and Evaluation Nadia N. Hansel, MD, MPH
Kaiser Permanente Southern California Professor of Medicine
Pasadena, California Division of Pulmonary and Critical Care Medicine
Chapter 41: Pulmonary Nodule Johns Hopkins University School of Medicine
Baltimore, Maryland
Bridget A. Graney, MD Chapter 63: COPD: Pathogenesis and Natural History
Instructor in Medicine
Division of Pulmonary Sciences and Critical Care Umur Hatipoğlu, MD, MBA
University of Colorado School of Medicine Associate Professor of Medicine
Aurora, Colorado Cleveland Clinic Lerner College of Medicine of Case
Chapter 90: Nonspecific Interstitital Pneumonitis and Western Reserve University
Other Idiopathic Interstitital Pneumonias Director, COPD Center
Respiratory Institute, Cleveland Clinic Foundation
Giacomo Grasselli, MD Cleveland, Ohio
Associate Professor Chapter 106: Air Travel
Department of Pathophysiology and Transplantation
University of Milan William R. Henderson, MD, PhD
Dipartimento di Anestesia-­Rianimazione e Emergenza Clinical Professor of Critical Care Medicine
Urgenza University of British Columbia Faculty of Medicine
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Staff Intensivist
Milan, Italy Division of Critical Care Medicine
Chapter 138: Extracorporeal Support of Gas Exchange Vancouver General Hospital
Vancouver, British Columbia, Canada
John R. Greenland, MD, PhD Chapter 11: Respiratory System Mechanics and Energetics
Associate Professor of Medicine
University of California San Francisco School of Medicine; Susanne Herold, MD, PhD
Staff Physician Professor of Medicine
Medical Service Universities of Giessen and Marburg Lung Center
San Francisco Veterans Administration Health Care Giessen, Germany
System Chapter 8: Regeneration and Repair
San Francisco, California
Chapter 72: Bronchiolitis Margaret S. Herridge, MSc, MD, MPH, FRCP(C)
Professor of Medicine
University of Toronto Faculty of Medicine;
David E. Griffith, MD Attending Physician
Professor of Medicine Division of Respirology and Critical Care
Division of Mycobacterial and Respiratory Infections University Health Network
National Jewish Health Toronto, Canada
Denver, Colorado
Chapter 134: Acute Respiratory Distress Syndrome
Chapter 55: Nontuberculous Mycobacterial Infections
 Contributors xvii

Robert Hiensch, MD David J. Horne, MD, MPH

Assistant Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
Icahn School of Medicine at Mount Sinai
New York, New York
Chapter 119: Sleep-­Disordered Breathing: A General
­Approach
Janet Hilbert, MD
Assistant Professor of Clinical Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
Yale School of Medicine
New Haven, Connecticut
Chapter 130: The Respiratory System and Neuromuscu-
lar Diseases
Nicholas S. Hill, MD, FPVRI
Professor of Medicine
Chief, Division of Pulmonary, Critical Care, and Sleep
Medicine
Tufts University Medical Center
Boston, Massachusetts
Chapter 132: Acute Ventilatory Failure
Antonia Ho, MBChB, PhD
Clinical Senior Lecturer
MRC-­University of Glasgow Centre for Virus Research
Institute of Infection, Immunity & Inflammation
Glasgow, United Kingdom
Chapter 46: Community-­Acquired Pneumonia
Stephanie M. Holm, MD, MPH
Assistant Clinical Professor of Medicine
Division of Occupational and Environmental Medicine
University of California San Francisco;
Co-­Director
Western States Pediatric Environmental Health Specialty
Units (WSPEHSU)
San Francisco, California;
Doctoral Student in Public Health
Division of Epidemiology
University of California Berkeley School of Public Health
Berkeley, California
Chapter 102: Indoor and Outdoor Air Pollution
Wynton Hoover, MD
Professor of Pediatrics
Division of Pulmonary and Sleep Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Chapter 68: Cystic Fibrosis: Diagnosis and Management
Associate Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
Adjunct Associate Professor of Global Health
Harborview Medical Center
University of Washington
Seattle, Washington
Chapter 54: Tuberculosis: Treatment of Drug-­Susceptible
and Drug-­Resistant
Richard L. Horner, PhD, FCAHS
Professor of Medicine and Physiology
Faculty of Medicine, University of Toronto;
Canada Research Chair in Sleep and Respiratory
Neurobiology
Fellow, Canadian Academy of Health Sciences
Toronto, Ontario, Canada
Chapter 117: Control of Breathing and Upper Airways
During Sleep
Connie C.W. Hsia, MD
Professor of Internal Medicine
Division of Pulmonary and Critical Care Medicine
University of Texas Southwestern Medical Center
Dallas, Texas
Chapter 128: Pulmonary Complications of Endocrine
Diseases
Laurence Huang, MD
Professor of Medicine
University of California San Francisco School of Medicine
Chief, HIV/AIDS Chest Clinic
Zuckerberg San Francisco General Hospital
San Francisco, California
Chapter 123: Pulmonary Complications of HIV Infection
Lindsey L. Huddleston, MD
Assistant Clinical Professor of Anesthesia
University of California San Francisco School of Medicine
San Francisco, California
Chapter 24: Ultrasonography: Advanced Applications and
Procedures
Robert C. Hyzy, MD
Professor of Medicine
Division of Pulmonary & Critical Care Medicine
University of Michigan Medical School
Director, Critical Care Medicine Unit
University of Michigan Hospital
Ann Arbor, Michigan
Chapter 137: Noninvasive Support of Oxygenation

Philip C. Hopewell, MD Yoshikazu Inoue, MD, PhD

Professor of Medicine
Director, Curry International TB Center
University of California San Francisco
San Francisco, California
Chapter 51: Tuberculosis Epidemiology and Prevention
Executive Director, Clinical Research Center
National Hospital Organization Kinki-­Chuo Chest Medical
Center
Sakai, Osaka, Japan
Chapter 97: Lymphangioleiomyomatosis
xviii Contributors

Claudia V. Jakubzick, PhD Marta Kaminska, MD, MSc

Associate Professor of Microbiology and Immunology
Dartmouth College
Hanover, New Hampshire
Chapter 15: Innate Immunity
Shijing Jia, MD
Assistant Professor of Medicine
Division of Pulmonary & Critical Care Medicine
University of Michigan Medical School
Ann Arbor, Michigan
Chapter 137: Noninvasive Support of Oxygenation
Kerri A. Johannson, MD, MPH
Assistant Professor of Medicine
University of Calgary Cumming School of Medicine
Calgary, Alberta, Canada
Chapter 91: Hypersensitivity Pneumonitis
Meshell Johnson, MD
Professor of Medicine
University of California San Francisco
Chief, Division of Pulmonary, Critical Care, and Sleep
Medicine
San Francisco VA Health Care System
San Francisco, California
Chapter 71: Large Airway Disorders
Associate Professor of Medicine
Division of Respiratory Medicine
McGill University Faculty of Medicine
Sleep Laboratory
McGill University Health Centre
Montreal, Quebec, Canada
Chapter 120: Obstructive Sleep Apnea
David A. Kaminsky, MD
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of Vermont Larner College of Medicine;
Attending Physician
Division of Pulmonary and Critical Care Medicine
University of Vermont Medical Center
Burlington, Vermont
Chapter 31: Pulmonary Function Testing: Physiologic
and Technical Principles
Chapter 39: Wheezing and Stridor
Midori Kato-­Maeda, MD, MS
Associate Professor of Medicine
University of California San Francisco
Zuckerberg San Francisco General Hospital
San Francisco, California
Chapter 51: Tuberculosis Epidemiology and Prevention

Clinton E. Jokerst, MD David A. Kaufman, MD

Assistant Professor of Radiology Assistant Professor of Medicine
Department of Diagnostic Imaging NYU Grossman School of Medicine
Mayo Clinic New York, New York
Scottsdale, Arizona Chapter 46a: COVID-­19
Chapter 20: Thoracic Radiology: Noninvasive
Diagnostic Imaging Kim M. Kerr, MD
Clinical Professor of Medicine
Kirk D. Jones, MD Division of Pulmonary, Critical Care, and Sleep Medicine
Professor of Pathology University of California San Diego School of Medicine
University of California San Francisco School of Medicine San Diego, California
San Francisco, California Chapter 86: Pulmonary Hypertension Due to Chronic
Chapter 22: Pathology: Neoplastic and Non-­neoplastic ­Thromboembolic Disease: Group 4
Lung Disease
Chapter 72: Bronchiolitis Shaf Keshavjee, MD, MSc, FRCSC, FACS
Professor of Surgery
Marc A. Judson, MD Division of Thoracic Surgery
Chief, Division of Pulmonary and Critical Care Medicine University of Toronto Faculty of Medicine
Albany Medical Center Surgeon-­in-­Chief
Albany, New York Sprott Department of Surgery
Chapter 93: Sarcoidosis Director, Toronto Lung Transplant Program
Director, Latner Thoracic Research Laboratories
University Health Network
Andre C. Kalil, MD, MPH Toronto, Ontario, Canada
Professor of Internal Medicine
Chapter 140: Lung Transplantation
Division of Infectious Diseases
University of Nebraska Medical Center
Omaha, Nebraska Fayez Kheir, MD, MSCR
Chapter 48: Hospital-­Acquired Pneumonia Assistant Professor of Medicine
Division of Pulmonary, Critical Care, and Environmental
Medicine
Tulane University School of Medicine
New Orleans, Louisiana
Chapter 40: Hemoptysis
 Contributors xix

Kristen M. Kidson, MD Kristine Konopka, MD

Clinical Instructor Assistant Professor of Pathology
Department of Anesthesiology, Pharmacology, and University of Michigan Medical School
Therapeutics Ann Arbor, Michigan
University of British Columbia Faculty of Medicine Chapter 80: Benign Lung Tumors
Vancouver, British Columbia, Canada
Chapter 11: Respiratory System Mechanics and Energetics Laura L. Koth, MD
Professor of Medicine
Kami Kim, MD Division of Pulmonary and Critical Care Medicine
Andor Szentivanyl Professor of Medicine University of California San Francisco
Director, Division of Infectious Disease & International San Francisco, California
Medicine Chapter 93: Sarcoidosis
University of South Florida Morsani College of Medicine
Global Health Infectious Disease Research Program Robert M. Kotloff, MD
University of South Florida College of Public Health Professor of Clinical Medicine
Tampa, Florida Pulmonary, Allergy, and Critical Care Division
Chapter 58: Parasitic Infections The Perelman School of Medicine at the University of
Pennsylvania
Suil Kim, MD, PhD Philadelphia, Pennsylvania
Assistant Professor Chapter 140: Lung Transplantation
Departments of Medicine, Physiology, and Pharmacology
Oregon Health & Science University Monica Kraft, MD
Director, Pulmonary Function Laboratory Robert and Irene Flinn Professor and Chair
VA Portland Health Care System Department of Medicine
Portland, Oregon College of Medicine, Tucson;
Chapter 71: Large Airway Disorders Deputy Director, Asthma and Airway Disease Research Center
University of Arizona Health Sciences
R. John Kimoff, MD, FRCP(C) Tucson, Arizona
Professor of Medicine Chapter 62: Asthma: Diagnosis and Management
Division of Respiratory Medicine
McGill University Faculty of Medicine Vidya Krishnan, MD, MHS
Director, Sleep Laboratory Associate Professor of Medicine
McGill University Health Centre Case Western Reserve University School of Medicine
Montreal, Quebec, Canada Associate Director, Center for Sleep Medicine
Chapter 120: Obstructive Sleep Apnea Division of Pulmonary, Critical Care, and Sleep Medicine
The MetroHealth System
Talmadge E. King Jr, MD Cleveland, Ohio
Dean, UCSF School of Medicine Chapter 118: Consequences of Sleep Disruption
Vice Chancellor for Medical Affairs
University of California San Francisco Lisa Kroon, PharmD
San Francisco, California Professor and Chair
Chapter 89: Idiopathic Pulmonary Fibrosis Department of Clinical Pharmacy
Chapter 90: Nonspecific Interstitial Pneumonitis and University of California San Francisco School of Pharmacy
Other Idiopathic Interstitial Pneumonias San Francisco, California
Chapter 66: Smoking Cessation
Georgios Kitsios, MD, PhD
Assistant Professor of Medicine Wolfgang M. Kuebler, MD, FERS, FAPS
Division of Pulmonary, Allergy, and Critical Care Professor of Physiology
Medicine Institute of Physiology
University of Pittsburgh School of Medicine Charite–Universitatsmedizin Berlin
Pittsburgh, Pennsylvania Berlin, Germany
Chapter 17: Microbiome Chapter 6: Vascular Biology

Jeffrey S. Klein, MD Elif Küpeli, MD, FCCP

A. Bradley Soule and John P. Tampas Green and Gold Professor of Medicine
Professor of Radiology Pulmonary Department
University of Vermont College of Medicine Baskent Üniversitesi Hastanesi Göğüs Hastalıkları AD
Burlington, Vermont Ankara, Turkey
Chapter 21: Thoracic Radiology: Invasive Diagnostic Chapter 26: Diagnostic Bronchoscopy: Basic
Imaging and Image-­Guided Interventions Techniques
xx Contributors
Ware G. Kuschner, MD
Chief, Pulmonary Section
VA Palo Alto Health Care System;
Professor of Medicine
Stanford University School of Medicine
Palo Alto, California
Chapter 103: Acute Responses to Toxic Exposures
Bart N. Lambrecht, MD, PhD
Department Director
Center for Inflammation Research (IRC)
Vlaams Instituut voor Biotechnologie
Zwijnaarde, Belgium;
Professor of Pulmonary Medicine
Ghent University
Ghent, Belgium
Chapter 60: Asthma: Pathogenesis and Phenotypes
Matthew R. Lammi, MD, MSCR
Associate Professor of Medicine
Division of Pulmonary/Critical Care and Allergy/
Immunology
Louisiana State University Health Sciences Center
New Orleans, Louisiana
Chapter 83: Pulmonary Hypertension: General Approach
Stephen E. Lapinsky, MBBCh, MSc, FRCPC
Professor of Medicine
University of Toronto Faculty of Medicine
Director, Intensive Care Unit
Mount Sinai Hospital
Toronto, Ontario, Canada
Chapter 129: The Lungs in Obstetric and Gynecologic
Diseases
Stephen C. Lazarus, MD, FCCP, FERS
Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Senior Investigator, Cardiovascular Research Institute
University of California San Francisco
San Francisco, California
Chapter 64: COPD: Diagnosis and Management
Jarone Lee, MD, MPH, FCCM
Associate Professor of Surgery and Emergency Medicine
Harvard Medical School
Medical Director, Blake 12 ICU
Trauma, Emergency Surgery, Surgical Critical Care
Department of Emergency Medicine
Massachusetts General Hospital
Boston, Massachusetts
Chapter 104: Trauma and Blast Injuries
Joyce S. Lee, MD
Associate Professor of Medicine
Division of Pulmonary Sciences and Critical Care
University of Colorado School of Medicine
Aurora, Colorado
Chapter 89: Idiopathic Pulmonary Fibrosis
Chapter 90: Nonspecific Interstitial Pneumonitis and
Other Idiopathic Interstitial Pneumonias
Warren L. Lee, MD, PhD, FRCP(C)
Associate Professor of Medicine
University of Toronto Faculty of Medicine;
Attending Physician
Medical-­Surgical Intensive Care Unit
Canada Research Chair, Mechanisms of Endothelial
Permeability
Staff Scientist, Keenan Research Center
St. Michael’s Hospital, Unity Health Network
Toronto, Canada
Chapter 134: Acute Respiratory Distress Syndrome
Won Y. Lee, MD
Associate Professor of Internal Medicine
Division of Pulmonary and Critical Care Medicine
University of Texas Southwestern Medical Center
Dallas, Texas
Chapter 128: Pulmonary Complications of Endocrine
Diseases
Y.C. Gary Lee, MBChB, PhD, FRACP, FCCP
Professor of Respiratory Medicine
Centre for Respiratory Health
University of Western Australia;
Consultant, Department of Respiratory Medicine
Director of Pleural Services
Sir Charles Gairdner Hospital
Perth, Australia
Chapter 111: Chylothorax
Chapter 114: Pleural Malignancy
Teofilo L. Lee-­Chiong Jr, MD
Professor of Medicine
University of Colorado School of Medicine
National Jewish Health
Denver, Colorado
Chapter 38: Chest Pain
Jonathan M. Lehman, MD, PhD
Instructor in Medicine
Division of Hematology and Oncology
Vanderbilt University Medical Center
Nashville, Tennessee
Chapter 73: Lung Cancer: Molecular Biology and Targets
Catherine Lemière, MD, MSc
Professor of Medicine
University of Montréal Faculty of Medicine
Chest Physician
Department of Medicine
Sacré-­Coeur de Montréal Hospital
Montréal, Canada
Chapter 100: Asthma in the Workplace
Robert J. Lentz, MD
Assistant Professor of Medicine and Thoracic Surgery
Vanderbilt University Medical Center
Nashville, Tennessee
Chapter 116: Mediastinitis and Fibrosing Mediastinitis
 Contributors xxi

Richard W. Light, MD Nicole Lurie, MD, MSPH

Professor of Medicine Strategic Advisor to the CEO
Division of Allergy, Pulmonary, and Critical Care Medicine Coalition for Epidemic Preparedness Innovations (CEPI)
Vanderbilt University School of Medicine Oslo, Norway
Nashville, Tennessee Chapter 59: Outbreaks, Pandemics, and Bioterrorism
Chapter 108: Pleural Effusion
Charles-­Edouard Luyt, MD, PhD
Andrew H. Limper, MD Professor
Associate Dean for Practice Transformation Medical Intensive Care Unit
Annenberg Professor of Pulmonary Research Pitié-­Salpêtrière Hospital
Department of Internal Medicine Paris, France
Director, Thoracic Diseases Research Unit Chapter 49: Ventilator-­Associated Pneumonia
Mayo Clinic College of Medicine
Rochester, Minnesota Stuart M. Lyon, MBBS, FRANZCR, EBIR
Chapter 99: Drug-­Induced Pulmonary Disease Associate Professor of Radiology
Monash University
Michael S. Lipnick, MD Melbourne, Australia;
Associate Professor of Anesthesia and Perioperative Care Associate Professor of Radiology
University of California San Francisco School of Medicine Monash Health
Dive Medical Officer Ormond, Australia
California Academy of Sciences Chapter 111: Chylothorax
San Francisco, California
Chapter 107: Diving Medicine Roberto F. Machado, MD
Dr. Calvin H. English Professor of Medicine
Stanley Yung-­Chuan Liu, MD, DDS, FACS Chief, Division of Pulmonary, Critical Care, Sleep, and
Assistant Professor of Otolaryngology Occupational Medicine
Assistant Professor of Plastic and Reconstructive Surgery, Indiana University School of Medicine
by Courtesy Indianapolis, Indiana
Co-­director, Sleep Surgery Fellowship Chapter 127: Pulmonary Complications of Hematologic
Department of Otolaryngology ­Diseases
Stanford University School of Medicine;
Chief, Maxillofacial Surgery Lisa A. Maier, MD, MSPH, FCCP
Stanford Health Care Professor of Medicine
Stanford, California Chief, Division of Environmental and Occupational Health
Chapter 122: Sleep-­Disordered Breathing: Treatment National Jewish Health
University of Colorado, Colorado School of Public Health
James E. Loyd, MD Denver, Colorado
Professor of Medicine Chapter 35: Evaluation of Respiratory Impairment and
Rudy W. Jacobson Chair in Pulmonary Medicine Disability
Division of Allergy, Pulmonary, and Critical Care Medicine
Vanderbilt University Medical Center
Atul Malhotra, MD
Nashville, Tennessee Peter C. Farrell Presidential Chair in Respiratory Medicine
Chapter 116: Mediastinitis and Fibrosing Mediastinitis Research Chief of Pulmonary and Critical Care Medicine
Director of Sleep Medicine
Njira Lugogo, MD University of California San Diego School of Medicine
Associate Professor of Medicine San Diego, California
Division of Pulmonary, Critical Care Medicine Chapter 117: Control of Breathing and Upper Airways
University of Michigan Medical School During Sleep
Ann Arbor, Michigan
Chapter 62: Asthma: Diagnosis and Management Thomas R. Martin, MD
Emeritus Professor of Medicine
Andrew M. Luks, MD University of Washington School of Medicine
Professor of Medicine Seattle, Washington;
Division of Pulmonary, Critical Care, and Sleep Medicine Global Head, Respiratory ­Therapeutic Area
University of Washington School of Medicine Global Drug Development
Seattle, Washington Novartis Pharmaceuticals
Chapter 33: Exercise Testing East Hanover, New Jersey
Chapter 105: High Altitude Chapter 15: Innate Immunity
xxii Contributors

Nick A. Maskell, DM, FRCP Anna M. May, MD, MS

Academic Respiratory Unit Assistant Professor
Translational Health Sciences Staff, Sleep Medicine Division
University of Bristol Medical School; Staff, Pulmonary and Critical Care Division
Respiratory Department Staff, Research Division
North Bristol NHS Trust VA Northeast Ohio Healthcare System;
Bristol, United Kingdom Staff, Division of Pulmonary, Critical Care, and Sleep
Chapter 109: Pleural Infections Medicine
University Hospitals Cleveland Medical Center
Pierre P. Massion, MD Staff, School of Medicine
Professor of Medicine, Cancer Biology, Radiology, and Case Western Reserve University
Radiological Sciences Cleveland, Ohio
Division of Allergy, Pulmonary, and Critical Care Chapter 122: Sleep-­Disordered Breathing: Treatment
Medicine
Vanderbilt University School of Medicine Annyce S. Mayer, MD, MSPH
Director, Cancer Early Detection and Prevention Initiative Associate Professor of Medicine
Co-­leader, Cancer Health Outcomes and Control Research Division of Environmental and Occupational Health
Program National Jewish Health
Vanderbilt Ingream Cancer Center University of Colorado, Colorado School of Public Health
Nashville, Tennessee Denver, Colorado
Chapter 73: Lung Cancer: Molecular Biology and Chapter 35: Evaluation of Respiratory Impairment and
Targets ­Disability

Stephen C. Mathai, MD, MHS Peter J. Mazzone, MD, MPH, FCCP

Associate Professor of Medicine Clinical Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine Case Western Reserve University School of Medicine;
Johns Hopkins University School of Medicine Director, Lung Cancer Program
Baltimore, Maryland Respiratory Institute
Chapter 83: Pulmonary Hypertension: General Cleveland Clinic
Approach Cleveland, Ohio
Chapter 75: Lung Cancer: Screening
Scott M. Matson, MD
Assistant Professor of Medicine Stuart B. Mazzone, PhD
Division of Pulmonary, Critical Care, and Sleep Medicine Professor of Neuroscience
University of Kansas School of Medicine Department of Anatomy and Neuroscience
Kansas City, Kansas University of Melbourne
Chapter 94: Diffuse Alveolar Hemorrhage Parkville, Victoria, Australia
Chapter 37: Cough
Michael A. Matthay, MD
Professor of Medicine and Anesthesia Cormac McCarthy, MD, PhD
Cardiovascular Research Institute Associate Professor of Medicine
University of California San Francisco University College Dublin
San Francisco, California Consultant Respiratory Physician
Chapter 133: Pulmonary Edema St. Vincent’s Hospital Group
Dublin, Ireland
Richard A. Matthay, MD Chapter 98: Pulmonary Alveolar Proteinosis Syndrome
Professor Emeritus and Senior Research Scientist in
Medicine F. Dennis McCool, MD
Yale School of Medicine Professor of Medicine
New Haven, Connecticut Division of Pulmonary and Critical Care Medicine
Chapter 38: Chest Pain Alpert Medical School of Brown University
Providence, Rhode Island
Chapter 130: The Respiratory System and Neuromuscu-
lar Diseases
Chapter 131: The Respiratory System and Chest Wall
Diseases
 Contributors xxiii

Francis X. McCormack, MD Nuala J. Meyer, MD, MS

Taylor Professor and Director Associate Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine Division of Pulmonary, Allergy, and Critical Care Medicine
University of Cincinnati College of Medicine Perelman School of Medicine at the University of
Cincinnati, Ohio Pennsylvania
Chapter 97: Lymphangioleiomyomatosis Philadelphia, Pennsylvania
Chapter 133: Pulmonary Edema
Meredith C. McCormack, MD, MHS
Associate Professor of Medicine Isabel C. Mira-­Avendano, MD
Division of Pulmonary and Critical Care Medicine Assistant Professor of Medicine
Johns Hopkins University School of Medicine Mayo Clinic Florida
Baltimore, Maryland Jacksonville, Florida
Chapter 10: Ventilation, Blood Flow, and Gas Exchange Chapter 95: Pulmonary Langerhans Cell Histiocytosis
and Other Rare Diffuse Infiltrative Lung Diseases
David McCulley, MD
Assistant Professor of Pediatrics Gita N. Mody, MD, MPH
University of Wisconsin School of Medicine Assistant Professor of Surgery
Madison, Wisconsin Division of Cardiothoracic Surgery
Chapter 2: Lung Growth and Development University of North Carolina School of Medicine
Chapel Hill, North Carolina
Bryan J. McVerry, MD Chapter 77: Lung Cancer: Treatment
Associate Professor of Medicine, Environmental and Occu-
pational Health, and Clinical and Translational Science Babak Mokhlesi, MD, MSc
Division of Pulmonary, Allergy, and Critical Care Medicine Professor of Medicine
University of Pittsburgh School of Medicine Section of Pulmonary and Critical Care
Pittsburgh, Pennsylvania Director, Sleep Disorders Center
Chapter 17: Microbiome Director, Sleep Medicine Fellowship Program
The University of Chicago Pritzker School of Medicine
Reena Mehra, MD, MS, FCCP, FAASM, FAHA Chicago, Illinois
Professor of Medicine Chapter 45: Hypercapnia
Cleveland Clinic Lerner College of Medicine of Case
­Western Reserve University Alison Morris, MD, MS
Director, Sleep Disorders Research, Neurologic Institute Professor of Medicine
Staff, Respiratory Institute Division Chief, Pulmonary, Allergy, and Critical Care
Staff, Heart and Vascular Institute Medicine
Staff, Department of Molecular Cardiology, Lerner Director, Center for Medicine and the Microbiome
Research Institute University of Pittsburgh School of Medicine
Cleveland Clinic Pittsburgh, Pennsylvania
Cleveland, Ohio Chapter 17: Microbiome
Chapter 122: Sleep-­Disordered Breathing: Treatment
Amy E. Morris, MD
Atul C. Mehta, MBBS, FACP, FCCP Associate Professor of Medicine
Buoncore Family Endowed Chair in Lung Transplantation Division of Pulmonary, Critical Care, and Sleep Medicine
Professor of Medicine University of Washington School of Medicine
Lerner College of Medicine Seattle, Washington
Staff Physician Chapter 23: Ultrasonography: Principles and Basic
Respiratory Institute ­Thoracic and Vascular Imaging
Cleveland Clinic
Cleveland, Ohio Timothy A. Morris, MD
Chapter 26: Diagnostic Bronchoscopy: Basic Techniques Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Mark L. Metersky, MD University of California San Diego School of Medicine
Professor of Medicine Clinical Service Chief
Division of Pulmonary, Critical Care, and Sleep Medicine University of California San Diego Medical Center
University of Connecticut School of Medicine San Diego, California
Farmington, Connecticut Chapter 81: Pulmonary Thromboembolism: Presentation
Chapter 48: Hospital-­Acquired Pneumonia and Diagnosis
xxiv Contributors

Rory E. Morty, PhD Stephen L. Nishimura, MD

Department of Translational Pulmonology Professor of Pathology
University Hospital Heidelberg University of California San Francisco School of Medicine
Heidelberg, Germany San Francisco, California
Chapter 1: Anatomy Chapter 22: Pathology: Neoplastic and Non-­neoplastic
Lung Disease
Lakshmi Mudambi, MBBS
Assistant Professor of Medicine Joshua D. Nosanchuk, MD
Oregon Health & Science University Senior Associate Dean
Director, Interventional Pulmonology Professor of Medicine and Microbiology & Immunology
VA Portland Health Care System Albert Einstein College of Medicine
Portland, Oregon New York, New York
Chapter 71: Large Airway Disorders Chapter 56: Endemic Fungal Infections

John S. Munger, MD Thomas G. O’Riordan, MD, MPH

Associate Professor of Medicine and Cell Biology Vice President US Medical Affairs
New York University Grossman School of Medicine Respiratory Therapeutic Area Head
New York, New York GlaxoSmithKline
Chapter 46a: COVID-­19 Philadelphia, Pennsylvania
Chapter 13: Aerosols and Drug Delivery
Mohammed Munavvar, MD, DNB, FRCP(Lon),
FRCP(Edin) Victor Enrique Ortega, MD, PhD
Consultant Chest Physician Associate Professor of Medicine
Department of Respiratory Medicine Center for Precision Medicine
Lancashire Teaching Hospitals Wake Forest School of Medicine
Preston, United Kingdom Winston-­Salem, North Carolina
Chapter 29: Thoracoscopy Chapter 60: Asthma: Pathogenesis and Phenotypes

Payam Nahid, MD, MPH Justin R. Ortiz, MD, MS, FCCP

Associate Professor of Medicine
Professor of Medicine
Center for Vaccine Development and Global Health
Division of Pulmonary and Critical Care Medicine
Department of Medicine
University of California San Francisco Center for
University of Maryland School of Medicine
Tuberculosis
Baltimore, Maryland
University of California San Francisco School of Medicine
Zuckerberg San Francisco General Hospital Chapter 47: Influenza
San Francisco, California
Chapter 54: Tuberculosis: Treatment of Drug-­Susceptible Sushmita Pamidi, MD, MSc
Assistant Professor of Medicine
and Drug-­Resistant
Division of Respiratory Medicine
McGill University Faculty of Medicine
Catherine Nelson-­Piercy, MBBS, MA, FRCP, FRCOG Sleep Laboratory
Professor of Obstetric Medicine McGill University Health Centre
Women’s Health Academic Centre Montreal, Quebec, Canada
King’s Health Partners Chapter 120: Obstructive Sleep Apnea
Consultant Obstetric Physician
Women’s Health Service
Guy’s & St Thomas’ Foundation Trust
Nicholas J. Pastis, MD, FCCP
Professor of Medicine
Consultant Obstetric Physician
Division of Pulmonary and Critical Care
Queen Charlotte’s and Chelsea Hospital
Medical University of South Carolina
Imperial College Healthcare Trust
Section Chief, Pulmonary and Critical Care
London, United Kingdom
Ralph H. Johnson Veterans Administration Medical Center
Chapter 129: The Lungs in Obstetric and Gynecologic Charleston, South Carolina
Diseases Chapter 76: Lung Cancer: Diagnosis and Staging
Linda Nici, MD
Professor of Medicine
The Warren Alpert Medical School of Brown University
Chief, Pulmonary and Critical Care Medicine
Providence Veterans Affairs Medical Center
Providence, Rhode Island
Chapter 139: Pulmonary Rehabilitation
 Contributors xxv

Sanjay R. Patel, MD, MS Benjamin A. Pinsky, MD, PhD

Professor of Medicine, Epidemiology, and Clinical and Associate Professor
Translational Science Departments of Pathology and Medicine (Infectious
Division of Pulmonary Allergy and Critical Care Medicine Diseases)
University of Pittsburgh School of Medicine Stanford University School of Medicine
Pittsburgh, Pennsylvania Medical Director, Clinical Virology Laboratory
Chapter 118: Consequences of Sleep Disruption Stanford Health Care and Stanford Children’s Health
Stanford, California
Nicolò Patroniti, MD Chapter 19: Microbiologic Diagnosis of Lung Infection
Professor
Anesthesia and Intensive Care Steven D. Pletcher, MD
Ospedale Policlinico San Martino Professor and Director, Residency Training Program
IRCCS Department of Otolaryngology–Head and Neck Surgery
Department of Surgical Sciences and Integrated University of California San Francisco
Diagnostics (DISC) San Francisco, California
University of Genoa Chapter 70: Upper Airway Disorders
Genoa, Italy
Chapter 138: Extracorporeal Support of Gas Exchange Vikramaditya Prabhudesai, MBBS, MS, FRCR
Assistant Professor of Medicine
Steven A. Pergam, MD, MPH University of Toronto Faculty of Medicine;
Associate Professor Interventional Radiologist
Vaccine and Infectious Disease Division Department of Medical Imaging
Fred Hutchinson Cancer Research Center; St. Michael’s Hospital
Associate Professor of Medicine Toronto, Ontario, Canada
University of Washington School of Medicine; Chapter 88: Pulmonary Vascular Anomalies
Director, Infection Prevention
Seattle Cancer Care Alliance Loretta G. Que, MD
Seattle, Washington Professor of Medicine
Chapter 125: Pulmonary Complications of Stem Cell and Division of Pulmonary, Allergy, and Critical Care Medicine
Solid Organ Transplantation Duke University Health System
Durham, North Carolina
Antonio Pesenti, MD Chapter 62: Asthma: Diagnosis and Management
Professor of Anesthesia and Critical Care
Department of Pathophysiology and Transplantation Bryon D. Quick, MD
University of Milan Chair, Department of Pulmonary and Sleep Medicine
Director, Dipartimento di Anestesia–Rianimazione e Emer- Kaiser Permanente Oakland Medical Center
genza Urgenza Oakland, California
Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico Chapter 126: Pulmonary Complications of Abdominal
Milan, Italy Diseases
Chapter 138: Extracorporeal Support of Gas Exchange
Najib M. Rahman, BM, BCh, MA(Oxon), MSc, FRCP,
Michael C. Peters, MD, MAS DPhil
Assistant Professor of Medicine Professor of Respiratory Medicine
Division of Pulmonary and Critical Care Medicine Head, Oxford Pleural Unit
University of California San Francisco Director of Oxford Respiratory Trials Unit (ORTU)
San Francisco, California Nuffield Department of Medicine
Chapter 61: Asthma and Obesity University of Oxford
Oxford, United Kingdom
Kurt Pfeifer, MD, FACP, SFHM Chapter 29: Thoracoscopy
Professor of Medicine Chapter 110: Pneumothorax
Division of General Internal Medicine
Medical College of Wisconsin
Milwaukee, Wisconsin
J. Usha Raj, MD, MHA
Anjuli S. Nayak Professor of Pediatrics
Chapter 34: Preoperative Evaluation University of Illinois College of Medicine at Chicago
Chicago, Illinois
Jennifer A. Philips, MD, PhD Chapter 6: Vascular Biology
Associate Professor of Medicine
Co-­director, Division of Infectious Diseases
Washington University in St. Louis
St. Louis, Missouri
Chapter 52: Tuberculosis: Pathogenesis and Immunity
xxvi Contributors

Maria I. Ramirez, PhD Carolyn L. Rochester, MD

Associate Professor of Medicine Professor of Medicine
Division of Pulmonary, Allergy, and Critical Care Medicine Section of Pulmonary, Critical Care, and Sleep Medicine
Center for Translational Medicine Yale University School of Medicine
Jane and Leonard Korman Respiratory Institute Director, Yale COPD Program
Sidney Kimmel Medical College at Thomas Jefferson Director, Pulmonary Rehabilitation
University VA Connecticut Healthcare System
Philadelphia, Pennsylvania New Haven, Connecticut
Chapter 1: Anatomy Chapter 139: Pulmonary Rehabilitation
Chapter 5: Lung Mesenchyme
Jesse Roman, MD
Rishindra M. Reddy, MD Professor of Medicine
Associate Professor of Surgery Division of Pulmonary, Allergy, and Critical Care Medicine
Section of Thoracic Surgery Center for Translational Medicine
University of Michigan Medical School Jane and Leonard Korman Respiratory Institute
Ann Arbor, Michigan Sidney Kimmel Medical College at Thomas Jefferson
Chapter 79: Metastatic Malignant Tumors University
Philadelphia, Pennsylvania
Elizabeth F. Redente, PhD Chapter 5: Lung Mesenchyme
Associate Professor of Pediatrics
Division of Cell Biology Alexandra Rose, MD
National Jewish Health Assistant Clinical Professor of Medicine
Denver, Colorado Division of Pulmonary and Critical Care Medicine
Chapter 15: Innate Immunity University of California San Diego School of Medicine
San Diego, California
Hasina Outtz Reed, MD, PhD Chapter 81: Pulmonary Thromboembolism: Presentation
Assistant Professor of Medicine and Diagnosis
Division of Pulmonary and Critical Care Medicine
Weill Cornell Medicine Clark A. Rosen, MD
New York, New York Lewis Francis Morrison, MD, Endowed Chair in
Chapter 7: Lymphatic Biology Laryngology
Professor, Department of Otolaryngology–Head and Neck
R. Lee Reinhardt, PhD Surgery
Associate Professor of Biomedical Research Chief, Division of Laryngology
National Jewish Health Co-­Director, UCSF Voice and Swallowing Center
Department of Immunology and Microbiology University of California San Francisco
University of Colorado Anschutz Medical Campus San Francisco, California
Aurora, Colorado Chapter 70: Upper Airway Disorders
Chapter 16: Adaptive Immunity
John M. Routes, MD
David W.H. Riches, PhD Professor of Pediatrics, Medicine, and Microbiology and
Professor of Medicine and Immunology Immunology
Division of Pulmonary Sciences and Critical Care Medicine Medical College of Wisconsin
University of Colorado Anschutz Medical Campus Milwaukee, Wisconsin
Aurora, Colorado; Chapter 124: Pulmonary Complications of Primary
Professor and Division Head ­Immunodeficiencies
Program in Cell Biology
National Jewish Health Steven M. Rowe, MD, MSPH
Denver, Colorado Professor of Medicine
Chapter 15: Innate Immunity University of Alabama at Birmingham School of Medicine
Birmingham, Alabama
M. Patricia Rivera, MD Chapter 67: Cystic Fibrosis: Pathogenesis and Epidemiol-
Professor of Medicine ogy
Division of Pulmonary and Critical Care Medicine Chapter 68: Cystic Fibrosis: Diagnosis and Management
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Chapter 77: Lung Cancer: Treatment
 Contributors xxvii

Clodagh M. Ryan, MBBCh, BAO, MD, FRCPC David A. Schwartz, MD

Assistant Professor of Medicine Chair and Professor
Centre for Sleep Medicine and Circadian Biology Department of Medicine
University of Toronto Faculty of Medicine; Professor of Immunology
Division of Respirology University of Colorado Anschutz Medical Campus
University Health Network Aurora, Colorado
Toronto Rehabilitation Institute Chapter 9: Genetics of Lung Disease
Toronto General Hospital
Toronto, Ontario, Canada Richard M. Schwartzstein, MD
Chapter 121: Central Sleep Apnea Ellen and Melvin Gordon Professor of Medicine and
­Medical Education
Jay H. Ryu, MD Harvard Medical School
Professor of Medicine Executive Director, Carl J. Shapiro Institute for Education
Division of Pulmonary and Critical Care Medicine and Research
Mayo Clinic Alix College of Medicine Chief, Division of Pulmonary, Critical Care, and Sleep
Rochester, Minnesota Medicine
Chapter 89: Idiopathic Pulmonary Fibrosis Vice President for Education
Beth Israel Deaconess Medical Center
Sarah Sanghavi, MD Boston, Massachusetts
Clinical Assistant Professor of Medicine Chapter 36: Dyspnea
Department of Medicine
Division of Nephrology Marvin I. Schwarz, MD
University of Washington School of Medicine Professor of Medicine
Veterans Affairs Puget Sound Health Care System Pulmonary Sciences and Critical Care Medicine
Seattle, Washington University of Colorado School of Medicine
Chapter 12: Acid-­Base Balance Aurora, Colorado
Chapter 94: Diffuse Alveolar Hemorrhage
Kathleen F. Sarmiento, MD, MPH
Associate Professor of Medicine Moisés Selman, MD
Division of Pulmonary, Critical Care, and Sleep Medicine Distinguished Investigator
University of California San Francisco Research Unit
San Francisco VA Healthcare System Instituto Nacional de Enfermedades Respiratorias
San Francisco, California Mexico City, Mexico
Chapter 119: Sleep-­Disordered Breathing: A General Chapter 89: Idiopathic Pulmonary Fibrosis
­Approach
Neomi Shah, MD, MPH
Jennifer L. Saullo, MD, PharmD Associate Professor of Medicine
Assistant Professor of Medicine Division of Pulmonary, Critical Care, and Sleep Medicine
Division of Infectious Diseases Icahn School of Medicine at Mount Sinai
Duke University Medical Center New York, New York
Durham, North Carolina Chapter 119: Sleep-­Disordered Breathing: A General
Chapter 57: Fungal Infections: Opportunistic ­Approach

Robert B. Schoene, MD Rupal J. Shah, MD, MSCE

Sound Physicians Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine Division of Pulmonary, Allergy, and Critical Care Medicine
St Mary’s Medical Center University of California San Francisco School of Medicine
San Francisco, California San Francisco, California
Chapter 105: High Altitude Chapter 43: Aspiration

Gregory L. Schumaker, MD Priya B. Shete, MD, MPH

Assistant Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
Tufts University School of Medicine;
Director, Medical ICU
Chief, Critical Care Section
Lowell General Hospital
Boston, Massachusetts
Chapter 132: Acute Ventilatory Failure
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of California San Francisco Center for
Tuberculosis
University of California San Francisco School of Medicine
San Francisco, California
Chapter 53: Tuberculosis: Clinical Manifestations and
­Diagnosis
xxviii Contributors

Samira Shojaee, MD, MPH Eric J. Sorscher, MD

Associate Professor of Medicine Professor of Pediatrics
Fellowship Director, Interventional Pulmonology Program Emory University School of Medicine
Division of Pulmonary and Critical Care Medicine Atlanta, Georgia
Virginia Commonwealth University Chapter 67: Cystic Fibrosis: Pathogenesis and Epidemiol-
Richmond, Virginia ogy
Chapter 28: Therapeutic Bronchoscopy: Interventional Chapter 68: Cystic Fibrosis: Diagnosis and Management
­Techniques
Renee D. Stapleton, MD, PhD
Gerard A. Silvestri, MD, MS, FCCP Professor of Medicine
Professor of Medicine Division of Pulmonary and Critical Care Medicine
Division of Pulmonary and Critical Care Medicine University of Vermont Larner College of Medicine
Medical University of South Carolina Burlington, Vermont
Charleston, South Carolina Chapter 141: End-­of-­Life Care in Respiratory Failure
Chapter 76: Lung Cancer: Diagnosis and Staging
Daniel Sterman, MD
Jonathan P. Singer, MD, MS Professor of Medicine and Cardiothoracic Surgery
Associate Professor of Medicine New York University Grossman School of Medicine
Division of Pulmonary, Critical Care, Allergy, and Sleep New York, New York
Medicine Chapter 114: Pleural Malignancy
University of California San Francisco School of Medicine
San Francisco, California Shelby J. Stewart, MD
Chapter 72: Bronchiolitis Assistant Professor of Thoracic Surgery
University of Maryland School of Medicine
Christopher G. Slatore, MD, MS Baltimore, Maryland
Investigator Chapter 113: Hemothorax
Center to Improve Veteran Involvement in Care
VA Portland Health Care System James K. Stoller, MD, MS
Associate Professor of Medicine Jean Wall Bennett Professor of Medicine
Division of Pulmonary and Critical Care Medicine Samson Global Leadership Academy Endowed Chair
Oregon Health & Science University Cleveland Clinic Lerner College of Medicine of Case
Portland, Oregon ­Western Reserve University
Chapter 41: Pulmonary Nodule Staff, Respiratory Institute
Cleveland Clinic
Gerald C. Smaldone, MD, PhD Cleveland, Ohio
Professor of Medicine, Physiology, and Biophysics Chapter 106: Air Travel
State University of New York at Stony Brook
Chief, Division of Pulmonary, Critical Care, and Sleep Xin Sun, PhD
Medicine Professor of Pediatrics
Stony Brook University Medical Center University of California San Diego School of Medicine
Stony Brook, New York San Diego, California
Chapter 13: Aerosols and Drug Delivery Chapter 2: Lung Growth and Development

Gerald W. Smetana, MD, MACP Bernie Y. Sunwoo, MBBS

Professor of Medicine
Harvard Medical School
Attending Physician
Division of General Medicine and Primary Care
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Chapter 34: Preoperative Evaluation
George M. Solomon, MD
Associate Professor of Medicine
Division of Pulmonary, Allergy, and Critical Care
University of Alabama at Birmingham School of Medicine
Birmingham, Alabama
Chapter 67: Cystic Fibrosis: Pathogenesis and Epidemiology
Chapter 68: Cystic Fibrosis: Diagnosis and Management
Chapter 69: Bronchiectasis
Associate Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
University of California San Diego School of Medicine
San Diego, California
Chapter 45: Hypercapnia
Daniel A. Sweeney, MD
Associate Professor of Medicine
University of California San Diego School of Medicine
San Diego, California
Chapter 24: Ultrasonography: Advanced Applications and
Procedures
 Contributors xxix

Erik R. Swenson, MD George E. Tzelepis, MD

Professor of Medicine, Physiology, and Biophysics Professor of Medicine
Department of Medicine National and Kapodistrian University of Athens Medical
Division of Pulmonary Medicine and Critical Care School
University of Washington School of Medicine Athens, Greece
Veterans Affairs Puget Sound Health Care System Chapter 131: The Respiratory System and Chest Wall
Seattle, Washington Diseases
Chapter 12: Acid-­Base Balance
Chapter 105: High Altitude Anatoly Urisman, MD, PhD
Assistant Professor of Pathology
Nichole T. Tanner, MD, MSCR, FCCP University of California San Francisco School of Medicine
Associate Professor of Medicine San Francisco, California
Division of Pulmonary and Critical Care Medicine Chapter 22: Pathology: Neoplastic and Non-­neoplastic
Medical University of South Carolina; Lung Disease
Staff Pulmonologist
Ralph H. Johnson Veteran Affairs Hospital Olivier Vandenplas, MD, PhD
Charleston, South Carolina Professor of Medicine
Chapter 41: Pulmonary Nodule Department of Chest Medicine
Chapter 75: Lung Cancer: Screening Mont-­Godinne University Hospital Center
Catholic University of Louvain
Lynn Tanoue, MD Yvoir, Belgium
Professor and Vice Chair for Clinical Affairs Chapter 100: Asthma in the Workplace
Department of Internal Medicine
Section of Pulmonary, Critical Care, and Sleep Medicine Karen B. Van Hoesen, MD
Yale School of Medicine Clinical Professor of Emergency Medicine
New Haven, Connecticut Associate Dean for Health Sciences Faculty Affairs
Chapter 75: Lung Cancer: Screening University of California San Diego School of Medicine
Co-­Director, San Diego Center of Excellence in Diving
George R. Thompson III, MD San Diego, California
Associate Professor of Clinical Medicine Chapter 107: Diving Medicine
Division of Infectious Diseases
University of California Davis School of Medicine Thomas K. Varghese Jr, MD, MS
Davis, California Associate Professor of Surgery
Chapter 56: Endemic Fungal Infections Head, Section of General Thoracic Surgery
Co-­Director, Thoracic Oncology Program
Bruce C. Trapnell, MD Program Director, Cardiothoracic Surgery Residency
Professor of Medicine and Pediatrics University of Utah School of Medicine
University of Cincinnati College of Medicine Salt Lake City, Utah
Director, Translational Pulmonary Science Center Chapter 115: Mediastinal Tumors and Cysts
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio Robert Vassallo, MD
Chapter 98: Pulmonary Alveolar Proteinosis Syndrome Professor of Medicine
Mayo Clinic
Matthew Triplette, MD, MPH Rochester, Minnesota
Assistant Professor of Medicine Chapter 95: Pulmonary Langerhans Cell Histiocytosis
Division of Pulmonary, Critical Care, and Sleep Medicine and Other Rare Diffuse Infiltrative Lung Diseases
University of Washington School of Medicine;
Assistant Professor, Clinical Research Division James W. Verbsky, MD, PhD
Fred Hutchinson Cancer Research Center Associate Professor of Pediatrics and Microbiology and
Seattle, Washington Immunology
Chapter 115: Mediastinal Tumors and Cysts Medical College of Wisconsin
Milwaukee, Wisconsin
Melissa H. Tukey, MD, MSc Chapter 124: Pulmonary Complications of Primary
Department of Pulmonary and Critical Care ­Immunodeficiencies
Kaiser Permanente Oakland Medical Center
Oakland, California
Chapter 126: Pulmonary Complications of Abdominal
Diseases
xxx Contributors
Ajay Wagh, MD, MS, FCCP
Interventional Pulmonology Fellow
Division of Pulmonary and Critical Care Medicine
Northwestern Memorial Hospital
Chicago, Illinois
Chapter 27: Diagnostic Bronchoscopy: Advanced Tech-
niques (EBUS and Navigational)
Ryan Walsh, MD
Associate Professor of Radiology
University of Vermont Medical Center
Shelburne, Vermont
Chapter 21: Thoracic Radiology: Invasive Diagnostic
Imaging and Image-­Guided Interventions
David J. Weber, MD, MPH
Professor of Medicine, Pediatrics, and Epidemiology
University of North Carolina School of Medicine
Medical Director
Hospital Epidemiology and Occupational Health
Associate Chief Medical Officer
Department of Epidemiology
University of North Carolina Health Care
Chapel Hill, North Carolina
Chapter 59: Outbreaks, Pandemics, and
Bioterrorism
Ashley A. Weiner, MD, PhD
Assistant Professor of Radiation Oncology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Chapter 77: Lung Cancer: Treatment
Louis M. Weiss, MD, MPH
Professor of Pathology
Division of Parasitology and Tropical Medicine
Professor of Medicine
Division of Infectious Diseases
Albert Einstein College of Medicine
New York, New York
Chapter 58: Parasitic Infections
Athol U. Wells, MBChB, MD, FRCR, FRCP
Professor of Respiratory Medicine
Faculty of Medicine, National Heart & Lung Institute
Imperial College London;
Consultant Physician
Interstitial Lung Disease Unit
Royal Brompton Hospital
London, United Kingdom
Chapter 92: Connective Tissue Diseases
John B. West, MD, PhD, DSc
Professor of Medicine and Physiology
University of California San Diego School of Medicine
San Diego, California
Chapter 10: Ventilation, Blood Flow, and Gas
Exchange
T. Eoin West, MD, MPH, FCCP
Associate Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
University of Washington School of Medicine
Adjunct Associate Professor of Global Health
University of Washington Schools of Medicine and Public
Health
Seattle, Washington
Chapter 47: Influenza
Douglas B. White, MD, MAS
UPMC Endowed Chair of Ethics in Critical Care Medicine
Department of Critical Care Medicine
University of Pittsburgh School of Medicine
Director, Program on Ethics and Decision Making in Criti-
cal Illness
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
Chapter 141: End-­of-­Life Care in Respiratory Failure
Kevin L. Winthrop, MD, MPH
Professor of Infectious Diseases and Public Health
Department of Medicine
Oregon Health & Science University–Portland State
­University School of Public Health
Portland, Oregon
Chapter 55: Nontuberculous Mycobacterial Infections
David A. Wohl, MD
Professor of Medicine
Division of Infectious Diseases
Institute of Global Health and Infectious Diseases
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Chapter 59: Outbreaks, Pandemics, and Bioterrorism
Lisa F. Wolfe, MD
Associate Professor of Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
Northwestern University Feinberg School of Medicine
Chicago, Illinois
Chapter 130: The Respiratory System and Neuromuscu-
lar Diseases
Prescott G. Woodruff, MD, MPH
Professor of Medicine
Division of Pulmonary, Critical Care, Allergy, and Sleep
Medicine
Cardiovascular Research Institute
University of California San Francisco
San Francisco, California
Chapter 60: Asthma: Pathogenesis and Phenotypes
William Worodria, MBChB, MMed, PhD, MSc
Staff Physician
Department of Medicine
Mulago Hospital
Kampala, Uganda
Chapter 123: Pulmonary Complications of HIV Infection

D. Dante Yeh, MD, MHPE, FACS, FCCM
Associate Professor of Surgery
Department of Surgery
University of Miami Miller School of Medicine
Acute Care Surgeon
Jackson Memorial Hospital
Miami, Florida
Chapter 104: Trauma and Blast Injuries
Christina Yoon, MD, MPH, MAS
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
University of California San Francisco Center for
Tuberculosis
University of California San Francisco School of Medicine
San Francisco, California
Chapter 42: Positive Screening Test for Tuberculosis
Chapter 53: Tuberculosis: Clinical Manifestations and
­Diagnosis
VyVy N. Young, MD
Associate Professor of Clinical Otolaryngology
Department of Otolaryngology–Head and Neck Surgery
University of California San Francisco School of Medicine
San Francisco, California
Chapter 43: Aspiration
Contributors xxxi
William J. Zacharias, MD, PhD
Assistant Professor of Pediatrics and Internal Medicine
Divisions of Pulmonary Biology, Developmental Biology,
and Pulmonary and Critical Care Medicine
University of Cincinnati School of Medicine
Cincinnati, Ohio
Chapter 3: Alveolar Compartment
Alberto Zanella, MD
Department of Pathophysiology and Transplantation
University of Milan
Dipartimento di Anestesia-­Rianimazione e Emergenza
Urgenza
Fondazione IRCCS Ca’ Granda–Ospedale Maggiore
Policlinico
Milan, Italy
Chapter 138: Extracorporeal Support of Gas Exchange
Preface to the Seventh Edition
This seventh edition of the Textbook represents the first
major reorganization since the first edition in 1988. You
will notice many changes in structure and content, all
aimed to enhance its readability and educational value.
There are two major changes. The first is that the num-
ber of chapters has been increased from 106 in the sixth edi-
tion to the current 142. This strategic change enabled us to
create more focused shorter chapters, which we hope are
easier to find and to read. We were able to bring new chap-
ters out of their hiding places under other headings (e.g.,
Influenza, Idiopathic Pulmonary Fibrosis, and Pneumotho-
rax), to create new chapters on topics not directly covered
before (e.g., Hypoxemia, Aspiration, and Air Travel), and to
cover entirely new topics (e.g., Microbiome and COVID-19).
The second major change was the creation of a new section
particularly with our trainees in mind, “The Evaluation of
Common Presentations in Respiratory Disease,” built on
the classic triad of Dyspnea, Cough, and Chest Pain. Seven
new chapters were added on topics ranging from Hypercar-
bia to Hemoptysis to Pulmonary Nodule, which we hope
will be a valuable resource for our readers. Other changes
to the Textbook are noteworthy: in particular, the sections
on Basic Science and on Sleep have been revamped, reflect-
ing the major rethinking of those topics in the last decade.
These changes were spearheaded by our exceptional
editorial board, with three new members. The makeup of
our editors is now equally women and men, a remarkable
change from the time in 2005 when I (V.C.B.) joined as the
inaugural woman. Our new editors have brought a fresh
outlook and diverse areas of expertise that helped chart this
new course. With these new editors have come a slew of new
authors. Of our 317 authors, we welcome almost 180 new
authors, either to take on new chapters or to take the place
of authors who have rotated off. Overall, our authors come
from 33 states of the United States and from 18 countries.
Here, too, we have increased the participation of women;
women now make up 32% of our authors, almost double
that in the previous edition (17%).
The printed textbook is a gateway to rich resources online.
While there are a whopping 900 figures in the printed text,
they are joined by others to make a total of 1650 figures
online, all available for download. The text is expanded by
an additional 25% online. A total of 190 videos and audio
clips are accessible online, popping up with just a click to the
link in the text. All the references are online, and each one
xxxii
links to the actual publication. Most importantly, the online
textbook will feature regular updates from our editors and
authors, with the aim of realizing a “living textbook.”
We wish to thank our valuable and skilled colleagues at
Elsevier, who made this herculean work possible. In partic-
ular, our thanks go to Jennifer Shreiner, who has remained
dedicated to the Textbook over the last three editions and
made this task a pleasure. In addition, Carrie Stetz had the
attention to detail and the high standards necessary to pro-
duce a lovely book. Thanks go also to Dolores Meloni and
Robin Carter. We also wish to thank the authors and editors
who contributed to the past editions.
The COVID-19 pandemic has loomed over us during this
project. Much of the book was written and edited during
lockdowns and hospital surges, with many of our authors
simultaneously juggling heavy frontline clinical and fam-
ily responsibilities with chapter deadlines. In recognition of
this momentous experience, we have added a chapter (46a)
devoted to the topic—a chapter that has been updated up to
the last moment and will continue to be updated frequently
online—and placed an image of the novel coronavirus on
our cover. The impact of the pandemic on our lives has
made the successful outcome of this project all the more
remarkable. A special thanks again to our authors and staff
for their outstanding efforts during this particularly difficult
time.
Sadly, Dr. Murray, who started this Textbook together
with Dr. Jay Nadel and guided it up to this point, died of
COVID-19 in March 2020. He remained committed to the
textbook until his last days. Over his illustrious career, he
taught many of us and inspired all of us to the highest call-
ings of teaching and caring for patients. This Textbook is
dedicated to him.
V. Courtney Broaddus, MD
Joel D. Ernst, MD
Talmadge E. King Jr, MD
Stephen C. Lazarus, MD, FCCP, FERS
Kathleen F. Sarmiento, MD, MPH
Lynn M. Schnapp, MD
Renee D. Stapleton, MD, PhD
Michael B. Gotway, MD
SECTION A
ANATOMY AND DEVELOPMENT OF
THE RESPIRATORY TRACT
1 ANATOMY
KURT H. ALBERTINE, phd, faaas, faaa • MARIA I. RAMIREZ, phd • RORY E. MORTY, phd
INTRODUCTION INNERVATION
GROSS AND SUBGROSS PLEURAL SPACE AND PLEURAL
ORGANIZATION MEMBRANES
AIRWAYS CELLULAR ANATOMY OF THE LUNG
BRONCHIAL CIRCULATION Airway Lining Cells
PULMONARY CIRCULATION Alveolar Lining Cells
TERMINAL RESPIRATORY UNITS Mesenchymal Cells
LYMPHATICS Neural Cells
INTRODUCTION
The lung has two essential, interdependent functions. One
essential function is ventilation-­ perfusion matching to
deliver oxygen (O2) to the body and to remove the carbon
dioxide (CO2) produced by the body (Fig. 1.1). The second
essential function is host defense against the onslaught of
airborne pathogens, chemicals, and particulates. These
essential functions are emphasized through the gross, sub-
gross, histologic, cellular, and molecular determinants of
the respiratory gas-­exchange process in the normal human
lung.1 Other secondary functions of the lung, which sup-
port the essential functions, are important, such as cellular
functions of surfactant synthesis, secretion and recycling,
mucociliary clearance, neuroendocrine signaling, and syn-
thesis and secretion of myriad molecules by the epithelial
and endothelial cells of the lung. The diversity of secondary
functions emphasizes the importance of the lung in homeo-
stasis. Finally, the widespread use of murine models in lung
research as surrogates for the human lung highlights the
need to understand the similarities and differences of the
lung between these species. The anatomic features that sup-
port the essential and secondary functions and comparative
anatomy topics are the focus of this chapter. In addition,
online supplemental digital videos linked to this chapter
provide views of lung movements related to changes in tidal
Hematopoietic and Lymphoid Cells
Pleural Cells
MOLECULAR ANATOMY OF THE
LUNG
COMPARISON OF THE LUNG OF
HUMANS AND MICE
KEY POINTS
volume, airway pressures, and respiratory rate. (Videos 1.1
to 1.5).
GROSS AND SUBGROSS
ORGANIZATION
The position of the lungs in the chest and in relationship to
the heart is shown in Fig. 1.2. Fig. 1.2A shows a midfron-
tal section through the thorax of a frozen human cadaver.
Fig. 1.2B shows a posterior-­anterior chest radiograph of a
normal human at functional residual capacity (FRC). The two
illustrations represent the extremes of the approaches to
study lung anatomy. On one hand, the cadaver lung (see
Fig. 1.2A) shows the gross anatomic arrangements and
relationships. The main distortion is that the lungs are at
low volume. The height of the lungs is only about 18 cm,
which is well below FRC height (see Fig. 1.2A). The dia-
phragm is markedly elevated in Fig. 1.2A, probably about
5 cm relative to its end-­expiratory position in life. Another
distortion is the abnormally wide pleural space. However,
that fixation shrinkage artifact serves as a useful reminder
that the lung is not normally attached to the chest wall. In
life, the separation between the parietal and visceral pleu-
rae is only several micrometers.2,3 On the other hand, the
chest radiograph (see Fig. 1.2B) shows that the height of
3
4 PART 1 • Scientific Principles of Respiratory Medicine
L (cm)
P
PV
PA
L
Br
C
Br
4 mm
Figure 1.1 Levels of oxygenation of blood in a frozen block of lung tis-
sue. Air is brought into the lung via the bronchus (Br). Pulmonary arterial
(PA) blood is dark purple because it is poorly oxygenated. Gas exchange
across the lung’s parenchyma (P) results in oxygenated pulmonary venous
(PV) blood, which is crimson. Also present in the peribronchovascular con-
nective tissue are bronchial arteries (arrows), cartilage (C), and lymphatics
(L). (Frozen sheep lung, unstained.)
the lung at FRC is approximately 24 cm, with the level of
the bifurcation of the pulmonary artery about halfway up
the lungs. The diaphragm is lower and flatter than in the
cadaver. However, the radiographic image is only a shadow
of dense structures.
In life, the human lungs weigh 900 to 1000 g, of which
nearly 40–50% is blood.4,5 At end-­expiration, the gas vol-
ume is about 2.5 L, whereas, at maximal inspiration, the
gas volume may be 6 L. Thus, overall lung density varies
from 0.30 g/mL at FRC to 0.14 g/mL at total lung capacity
(TLC). However, the density of the lung is not distributed
uniformly, being about 1 g/mL near the hilum and 0.1 g/
mL peripherally. If one likens each lung to a half cylinder,
more than 50% of all the lung’s alveoli are located in the
outer 30% of the lung radius (hilum to chest wall). This is
why the peripheral portion of the lung appears relatively
empty in the chest radiograph (see Fig. 1.2). Variability in
density also exists from top to bottom. In Fig. 1.2, the blood
vessels are more distended in the lower lung fields. The
increasing distention of vessels from apex to base also illus-
trates the increase in vascular distending pressures at the
rate of 1 cm H2O/cm height down the lung.
The composition of the various tissues that comprise the
lung is summarized in Table 1.1. An amazing point is how
little tissue is involved in the architecture of the alveolar
walls.6,7 However, this is as it should be because the major
physical obstacle to gas exchange is the slowness of O2 dif-
fusion through water.8,9 Thus, the alveolar walls must be
extremely thin. In fact, the thickness of the red blood cell
(RBC) forms a substantial portion of the air-­blood diffusion
pathway. Advantage was taken of this fact to separate the
carbon monoxide diffusing capacity measurement into two
components: the capillary blood volume and the membrane
diffusing capacity.10 (For a discussion of diffusing capacity,
see Chapter 31.)
The lung has two well-­defined interstitial connective
tissue compartments arranged in series, as described by
Hayek11 (Fig. 1.3). These are the parenchymal (alveolar
wall) interstitium and the loose binding (extra-­alveolar)
connective tissue (peribronchovascular sheaths, inter-
lobular septa, and visceral pleura). The connective
Lung Ht
18
T
PS
9
LA
A 0
24
PA 13
LA
9
B
0
Figure 1.2 Comparison views of the position of the lungs in the chest
and their relationship to the heart. (A) Midfrontal section through the
thorax of a frozen cadaver of a 35-­year-­old human. The cadaver was pre-
pared by routine embalming procedures, stored horizontally for 3 months
in 30% alcohol, and frozen in the horizontal position for 1 week at −20°C.
Frontal sections were cut with a band saw. Because the cadaver was pre-
served in the horizontal position, the weight of the abdominal organs com-
pressed the contents of the thoracic cavity. The domes of the diaphragm
(arrows) are elevated about 5 cm relative to their end-­expiratory position
in life. Pleural space (PS) width is artifactually enlarged; normally, in life it
is several micrometers in width. The trachea (T) is flanked on its left by the
aortic arch and on its right by the azygos vein. The left pulmonary artery
lies on the superior aspect of the left mainstem bronchus. Pulmonary veins
from the right lung enter the left atrium (LA), which is located about 7 cm
above the lung’s base. These structures at the root of the lungs caused
the esophagus to be cut twice as it follows a curved path behind them to
reach the stomach. (B) Chest radiograph of a normal human adult taken in
the upright position at functional residual capacity. The lung height (cm)
was measured from the costodiaphragmatic angle to the tubercle of the
first rib. The main pulmonary artery (PA) and LA are outlined. The vascu-
lar structures, especially the pulmonary veins, are more easily seen near
the base of the lung. This is partly because vascular distending pressures
are greater near the bottom. The density of the lung is also graded, being
higher at the bottom than the top and higher near the hilum than periph-
erally. (From Koritké JG, Sick H. Atlas of Sectional Human Anatomy. vol. 1: Head,
Neck, Thorax. Baltimore: Urban and Schwarzenberg; 1983:83.)
tissue fibrils (collagen, elastin, and reticulin) form a three-­
dimensional basket-­like structure around the alveoli and
airways (Fig. 1.4).12 This basket-­like arrangement allows
the lung to expand in all directions without develop-
ing excessive tissue recoil. Because the connective tissue
fibrils in the parenchymal interstitium are extensions of
the coarser fibers in the loose-­binding connective tissue,
stresses imposed at the alveolar wall level during lung
 1 • Anatomy 5

Table 1.1 Components of Normal Human Lung

PA IS
Volume or Mass Thickness
Component (mL) (μm) Reference TB
Gas 2400 9
RB
Tissue 900 4, 5 PV
Blood 400 5 AD
Lung 500 9
Support structures 225 6
Alveolar walls 275 6, 7
ALV
Epithelium 60 0.18 6, 7
Endothelium 50 0.10 6, 7
Interstitium 110 0.22 6, 7
Alveolar 55 7
macrophages
Figure 1.4 Illustration of the connective tissue support of the normal
human adult lung lobule. The weave of fibers composing the “elastic
continuum” is demonstrated. AD, alveolar duct; ALV, alveolus; IS, interstitial
space; PA, pulmonary artery; PV, pulmonary vein; RB, respiratory bronchi-
ole; TB, terminal bronchiole. (From Wright RR. Elastic tissue of normal and
emphysematous lungs. Am J Pathol. 1961;39:355–363.)

VP

ILS

CTS
PA
Br 2 mm
Figure 1.5 Accumulation of interstitial pulmonary edema in the
loose-binding interstitial spaces. The edema fluid accentuates the
loose-­binding (peribronchovascular) connective tissue spaces (CTS) that
surround the bronchi (Br) and pulmonary arteries (PA). Interstitial edema
also expanded the interlobular septa (ILS) that are contiguous with the con-
Figure 1.3 General plan depicting the interstitial connective tissue
nective tissue of the visceral pleura (VP). (Frozen sheep lung, unstained.)
compartments of the lung. All of the extra-alveolar support structures
(airways, blood vessels, interlobular septa, visceral pleura) are subsumed
under the term, loose-binding connective tissue. The alveolar walls’ inter-
stitium comprises the parenchymal interstitium. This organizational plan
of the lung follows the general organization of all organs. (From Hayek H.
The Human Lung. New York: Hafner; 1960:298–314.)

inflation are transmitted not only to adjacent alveoli, IC

which abut each other, but also to surrounding alveolar
ducts and bronchioles, and then to the loose-­binding con-
nective tissue supporting the whole lobule, and ultimately EL COL
to the visceral pleural surface (see Fig. 1.3). These rela-
tions become more apparent in certain pathologic condi-
tions. For example, in interstitial emphysema,13 air enters
the loose-­binding connective tissue and dissects along the *
peribronchovascular sheaths to the hilum and along the
0.5 µm
lobular septa to the visceral pleura. Interstitial pulmonary
edema fluid enters and moves along the same interstitial Figure 1.6 Structure of the interstitial compartment. The connective
pathways (Fig. 1.5).14 tissue compartment of the lung contains interstitial cells (IC; fibroblasts),
fibrils of collagen (COL), and bundles of elastin (EL). The bulk of the inter-
The bulk of the interstitium is occupied by a matrix of stitium, however, is occupied by matrix constituents (asterisk), such as gly-
proteoglycans (Fig. 1.6).15,16 Proteoglycans constitute a cosaminoglycans. (Human lung surgical specimen, transmission electron
complex group of gigantic polysaccharide molecules (≈30 microscopy.)
6 PART 1 • Scientific Principles of Respiratory Medicine

LP
M SM S
L
TB RB
G

CP
CT
G
G
PA
250 µm

Figure 1.7 Wall structure of a bronchus. The bronchial wall is composed

of mucosa (M), lamina propria (LP), smooth muscle (SM), and submucosa
(S). Seromucous glands (G) are located between the spiral bands of SM and
cartilaginous plates (CP). Diffuse lymphoid tissue (L) has infiltrated the lam-
ina propria and submucosa. (Human lung surgical specimen, right middle
lobar bronchus, 2-­μm–thick glycol methacrylate section, light microscopy.)
different core proteins, with great diversity of glycosamino-
glycan side chains) whose entanglements impart a gel-­like
structure to the interstitium. That structural role, although
essential, is not the sole role of these important molecules. A
growing view is emerging of the lung’s extracellular matrix
components as regulators of lung physiology, such as
determining epithelial cell phenotype; binding of and subse-
quent signaling by cytokines; chemokines and growth fac-
tors; and cell proliferation, migration, differentiation, and
apoptosis.17–24 In disease states, degradation products of
extracellular matrix components may activate the Toll-­like
receptor pathways (see discussion later), thus the degrada-
tion products may serve as endogenous sentinels of tissue
damage and initiators of innate immune responses.19,23–25
Within this gel-­like interstitium reside several varieties of
interstitial cells (contractile and noncontractile interstitial
cells,26,27 mast cells, plasma cells, and occasional leuko-
cytes). The remainder of the interstitium is composed of
laminin, collagens, elastin and reticulin fibrils, fibronectin,
and tenascin (see Fig. 1.6). (For more details on the lung
mesenchyme see Chapter 5.)
AIRWAYS
The airways, forming the connection between the out-
side world and the terminal respiratory units (TRUs), are
of central importance to lung function in health and dis-
ease.28,29 Intrapulmonary airways are divided into three
major groups: bronchi (conducting airways with cartilage)
(Fig. 1.7), membranous bronchioles (distal conducting air-
ways without cartilage) (Fig. 1.8), and respiratory bron-
chioles (distal airways participating to some extent in gas
exchange) (Fig. 1.9; Table 1.2). Bronchi, by definition, have
cartilage in their wall. The trachea, bronchi, and membra-
nous bronchioles peripherally to and including terminal
bronchioles (together the conducting airways) do not partici-
pate in respiratory gas exchange. Respiratory bronchioles
serve a dual function as airways and as part of the alveolar
volume that participates in respiratory gas exchange.29
The anatomic dead space, as measured by the single-­
breath nitrogen dilution technique, is approximately
30% of each tidal volume. Anatomically, this dead space
50 µm
Figure 1.8 Differences in wall structure of terminal bronchioles and
respiratory bronchioles. The wall of the terminal bronchiole (TB) is con-
structed of a single layer of ciliated, cuboidal epithelium that rests over
thin, discontinuous bands of smooth muscle and loose areolar connective
tissue (CT). In contrast, the wall of the respiratory bronchiole (RB) is only
partially lined by ciliated cuboidal epithelium (lower left). The remainder of
its wall is lined by squamous epithelium (upper right). The connective tissue
also surrounds the adjacent pulmonary arteriole (PA). (Human lung surgi-
cal specimen, 10-­μm–thick paraffin section, light microscopy.)
RB
AD
TB A
200 µm
A
A
A
RB
AD
A
B 200 µm
Figure 1.9 Longitudinal sections along membranous bronchioles. (A)
Diameter remains relatively constant along the terminal bronchiole (TB),
respiratory bronchiole (RB), and alveolar duct (AD). Alveoli (A) communi-
cate with the gas-­exchange duct. (B) This longitudinal section along an
RB and AD shows that their diameter is relatively constant and that both
gas-­exchange ducts communicate with clusters of alveoli (A). (Human lung
surgical specimen, 10-­μm–thick paraffin section, light microscopy.)
is accounted for principally by the volume of the extra-
pulmonary (upper) airways, including the nasopharynx,
trachea, and the intrapulmonary bronchi.30 The trachea
and bronchi are cartilaginous and do not change shape
substantially with ventilation. The membranous bron-
chioles (noncartilaginous airways of ≈1-­mm diameter or
less), although exceedingly numerous, are short. They
 1 • Anatomy 7

Table 1.2 Characteristics of Airway Generations in Humans

Airway Generation Generations Characteristic Role TRU Reference
Trachea 0 Cartilaginous Conducting 28, 29
Bronchi 1–3 Cartilaginous Conducting 28, 29
Bronchioles 4–13 Membranous Conducting 28, 29
Terminal bronchioles 14 Membranous Conducting 96
Respiratory bronchioles 16–18 Partially membranous Partially conducting and gas exchange Yes 96
Alveolar ducts 19–22 Gas exchange Yes 96
Alveoli 23 Gas exchange Yes 96

TRU, terminal respiratory unit.

consist of about five branching generations and end at

the terminal bronchioles. In contrast to the bronchi, the
membranous bronchioles are tightly embedded in the con- Brl Brl
nective tissue framework of the lung and therefore enlarge
passively as lung volume increases.31 Histologically, the
bronchioles down to and including the terminal bronchi-
oles ought to contribute about 25% to the anatomic dead
PA
space. In life, however, they contribute little because of
gas-­phase diffusion and mechanical mixing along the dis- PA
tal airways, resulting from the cardiac impulse (refer to
the supplemental videos on lung movements). By defini-
tion, the respiratory bronchioles and alveolar ducts par- 50 µm
ticipate in gas exchange and thus do not contribute to Figure 1.10 Cross-­sections of two bronchioles that would contribute
the anatomic dead space. The volume of the respiratory to increased airway resistance. On the left is a bronchiole (Brl) that is
bronchiole-­ alveolar duct system is approximately one-­ partially narrowed, evident by the folded and thick epithelium. The bron-
third of the total alveolar volume, and it is into this space chiole to the right is completely narrowed. Its lumen is obliterated by the
infolded epithelium. This bronchiole’s smooth muscle is thick (arrow), sug-
that the fresh-­air ventilation enters during inspiration. gesting that the narrowing is related to constriction of the smooth muscle.
Most airway resistance arises from the upper airways Each bronchiole is flanked by a pulmonary arteriole (PA). (Sheep lung,
and bronchi. Normally, the large airways are partially 5-­μm–thick paraffin section, light microscopy.)
constricted. The minimum airway diameter in the human
lung, about 0.5 mm, is reached at the level of the terminal
bronchioles; succeeding generations of exchange ducts
(respiratory bronchioles and alveolar ducts) are of constant
diameter (see Fig. 1.9).29,32 The functional significance of
centralized resistance is that the TRUs are regionally ven- CE
tilated chiefly in proportion to their individual distensibili-
ties (compliances) because most of their airway resistance
is common. This is demonstrated normally by the finding G
that regional lung ventilation is dependent primarily upon
the initial volumes of the alveoli. TRUs toward the top of the
lung, which are more expanded at FRC, do not receive as
great a share of the inspiratory volume as do the TRUs near
the bottom of the lung. B
1.0 µm
Airway diameter represents a balance between anatomic
dead space volume and airflow resistance. Airway diameter Figure 1.11 Cells constituting the bronchial epithelium. The arrows at
ought to be as small as possible to minimize anatomic dead the apical surface of the airway cells indicate the location of junctional com-
plexes between contiguous epithelial cells. The bronchial epithelium has
space and maximize efficient alveolar ventilation by reduc- ciliated epithelial cells (CE), goblet cells (G), and basal cells (B). Goblet cells
ing the dead space–to–tidal volume ratio, whereas airway have abundant mucous granules in the cytoplasm, and their apical surface
diameter ought to be as large as possible to minimize airway is devoid of cilia. Basal cells, as their name indicates, are located along the
resistance and the work of breathing. In disease, airways abluminal portion of the lining epithelium, adjacent to the basal lamina.
are often narrowed (Fig. 1.10), which increases resistance (Human lung surgical specimen, transmission electron microscopy.)
and the work of breathing.
The presence of apical junctional complexes between Apical junctional complexes consist of three elements:
airway epithelial cells (Fig. 1.11) has important functional zonula occludens (tight junction), zonula adherens, and mac-
implications for metabolically regulated secretion into and ula adherens (desmosome).33 Tight junctions serve two
absorption of electrolytes and water from the lining liquid. important functions: (1) restriction of passive diffusion by
8 PART 1 • Scientific Principles of Respiratory Medicine
blocking the lateral intercellular space and (2) polarization
of cellular functions (ion and water transport) between the
apical and basolateral membranes.34 Polarization of chlo-
ride and sodium transport allows the airway epithelium
either to secrete or absorb ions, with associated passive
water movement (see Chapter 3).
Trapping of foreign material, such as particulates or
bacteria, is accomplished by mucins. Mucins are complex
glycoproteins that form gels. MUC5AC and MUC5B are the
main gel-­forming mucins in human airways.35,36 MUC5AC
is produced by surface epithelia in proximal cartilaginous
airways.37 Normally, MUC5B is produced by airway glan-
dular cells37,38 but, in a variety of pulmonary diseases,
its cell source is expanded. Other mucins (e.g., MUC5B,
MUC7)38,39 become expressed by airway epithelial cells in
diseases, such as cystic fibrosis. In that disease, MUC5B is
produced by airway epithelial cells.40
Glands are limited to the submucosa of the bronchi.
Airway glands secrete water, electrolytes, and mucins into
the lumen. Studies of regulation of secretion in vivo and by
explant culture systems in vitro show that secretion can
be modulated by neurotransmitters, including choliner-
gic, adrenergic, and peptidergic transmitters,41,42 and by
inflammatory mediators, such as histamine,43 platelet-­
activating factor,44 and eicosanoids.45 The absence of air-
way glands and goblet cells distal to ciliated epithelial cells
makes teleologic sense because that arrangement should
minimize the flow of mucus backward into alveolar ducts
and alveoli.
Although most foreign material and immunologic stim-
uli are carried up the airways by mucociliary action, some
are cleared by the lymphatics. In addition, lymphoid tis-
sue is found within the lungs and referred to as inducible
bronchus-­associated lymphoid tissue (iBALT).46 These lym-
phoid aggregates are distributed along the tracheobron-
chial tree (see Fig. 1.7) and, to a lesser extent, along the
blood vessels.46–48 BALT in the human lung is called induc-
ible because it is not present at birth in humans or in germ-­
free animals but develops after antigenic stimulation.47,48
Lymphocytes in these structures are principally B cells,
which often form follicles.49 The presence of lymphocytes
along the airways provides a reminder that the respiratory
system is constantly challenged by airborne immunologic
stimuli. The tracheobronchial lymphoid tissue appears to
provide an important locus for both antibody-­mediated
and cell-­mediated immune responses.50 Another impor-
tant locus of immune response is provided by the epithelial
cells that line the airways and comprise the airway glands.
The importance of epithelial cells arises from their expres-
sion of Toll-­like receptors (TLRs), whose role is identification
of pathogen-­ associated molecular patterns.51 Activation
of TLRs leads to downstream signaling cascades involved
in mucin production, leukocyte recruitment, antimicro-
bial peptide production, and wound repair52–57 (see also
Chapter 15).
BRONCHIAL CIRCULATION
The trachea (and esophagus), mainstem bronchi, and pul-
monary vessels entering the lung (see Fig. 1.1), as well
as the visceral pleura in humans (see “Pleural Space and
BA BA
5 mm
Figure 1.12 Surface view of the visceral pleura. Yellow latex polymer
fills the rich network of the bronchial arteries (BA) and subsequent micro-
vascular network. Some bronchial arterioles flank lymphatics (arrow) that
comprise the superficial lymphatic plexus of the lung. (Sheep lung visceral
pleural surface.)
Pleural Membranes” toward the end of this chapter), are
supplied by the bronchial (systemic) blood circulation.58–60
Measurements of bronchial circulation, by microsphere
studies in animals, indicate that flow is 0.5–1.5% of cardiac
output and is predominantly to the large airways.58,59,61–64
The bronchial arteries arborize into bronchial capillaries
that form a network in the lamina propria (the underly-
ing connective tissue), in the submucosa, and in the region
external to the cartilage of bronchi, as well as in the lam-
ina propria of neighboring pulmonary arteries.65 Venous
blood from the trachea and large airways enters bronchial
venules, which converge to form bronchial veins that drain
into the azygos or hemiazygos veins. Thus, most bronchial
blood flow returns to the right side of the heart. Deeper in
the lung, however, bronchial blood passes via short anasto-
motic vessels into the pulmonary venules, thus reaching the
left side of the heart to contribute to the venous admixture.
The relationships among the bronchial, pulmonary, and
systemic arterial and venous circulations are diagrammed
in eFig. 1.1.
The bronchial circulation has enormous growth poten-
tial in contrast to the pulmonary circulation, which, after
childhood, is unresponsive to growth signals. As a result, the
bronchial circulation is the primary source of new vessels for
repair of tissue after lung injury. In long-­standing inflamma-
tory and proliferative diseases, such as bronchiectasis or car-
cinoma, bronchial blood flow may be greatly increased.59,66
Scar tissue and tumors greater than 1 mm in diameter receive
their blood supply via the bronchial circulation.67,68 As will
be discussed near the end of this chapter, the bronchial cir-
culation also supplies the visceral pleura of species that have
thick visceral pleura (Fig. 1.12), which includes humans.
PULMONARY CIRCULATION
In humans, the pulmonary artery enters each lung at the
hilum in a loose connective tissue sheath adjacent to the
main bronchus (see Fig. 1.1). The pulmonary artery trav-
els adjacent to and branches with each airway generation
(Fig. 1.13) down to the level of the respiratory bronchiole
(see Fig. 1.8). The anatomic arrangements of the pulmo-
nary arteries and the airways are a continual reminder
of the relationship between perfusion and ventilation

Br
PA
PA
Br
0.5 mm
Figure 1.13 Divisions of the pulmonary artery (PA) within the
lung. The PA divides and travels beside the bronchi and bronchioles (Br)
out to the respiratory bronchioles. Thus, at all airway generations, an inti-
mate relationship exists with pulmonary arterial generations. Note that the
loose-­binding (peribronchovascular) connective tissue sheaths are not dis-
tended, compared to the interstitial edema cuffs in Fig. 1.5. (Frozen normal
sheep lung, unstained.)
PV
A (left atrial pressure), would be −4 cm H2O near the top of
RB
AD
TB
PA
200 µm
Figure 1.14 Anatomy of terminal respiratory units. Terminal respira-
tory units (the physiologist’s alveolus) consist of the alveoli (A) and alveolar
ducts (AD) arising from a respiratory bronchiole (RB). Each unit is roughly
spherical, as suggested by the dashed outline. Pulmonary venous vessels
(PV) are peripherally located. PA, pulmonary artery; TB, terminal bron-
chiole. (Normal sheep lung, somewhat underinflated, 2-­μm–thick glycol
methacrylate section, light microscopy.)
that determines the efficiency of normal lung function.
Although the pulmonary veins also lie in loose connective
tissue sheaths adjacent to the main-­stem bronchus and pul-
monary artery at the hilum, once inside the lung they fol-
low Miller’s dictum that the veins will generally be found as
far away from the airways as possible.58 Peripherally, the
pulmonary arteries branch out into the TRU, whereas the
veins occupy the surrounding connective tissue envelope
(Fig. 1.14). Each small muscular pulmonary artery supplies
a specific volume of respiratory tissue, whereas each vein
drains portions of several such zones.
1 • Anatomy 9
Table 1.3 Quantitative Data on Intrapulmonary Blood
Vessels in Humans
Vessel Class Volume Surface
(With Diameter) (mL) Area (m2) Reference
Arteries (>500 μm) 68 0.4 69
Arterioles (13–500 μm) 18 1.0 69
Capillaries (10 μm) 60–200 50–70 70
Venules (13–500 μm) 13 1.2 71
Veins (>500 μm) 58 0.1 71
Considerable quantitative data about the pulmonary
circulation are available for the human lung (Table
1.3).69–71 Although most of the intrapulmonary blood
volume is in the larger vessels down to approximately 500
μm diameter, nearly all of the surface area is in the smaller
vessels. For example, the surface area of arterioles 20 to
500 μm in diameter exceeds that of the larger vessels by
a factor of two, and the maximal capillary surface area is
20 times that of all other vessels. Such impressive expan-
sion of surface area maximizes the area for respiratory gas
exchange.
Because the vertical height of the lung at FRC is about
24 cm (see Fig. 1.2), the pressure within the pulmonary
blood vessels varies by approximately 24 cm H2O over the
full height of the lung. Thus, if pulmonary arterial pressure
is taken as 20 cm H2O (15 mm Hg, 1.9 kPA)* at the level of
the main pulmonary artery, which is about halfway up the
height of the lung, pressure in the pulmonary arteries near
the top of the lung will be about 12 cm H2O, whereas pres-
sure in pulmonary arteries near the bottom will be about
36 cm H2O. Pulmonary venous pressure, which is about
8 cm H2O at the level of the pulmonary artery in midchest
the lung and +20 cm H2O at the bottom. In the normal
lung, the blood volume is greater at the bottom because of
increased luminal pressure, which expands those vessels
and increases their volume. This effect of distention also
decreases the contribution of the blood vessels at the bottom
of the lung to total pulmonary vascular resistance.
From birth through adulthood, the normal pulmonary
circulation is a low-­resistance circuit. The resistance is
distributed somewhat differently than in the systemic cir-
culation, where the major drop in resistance is across the
arterioles. In the pulmonary circulation, although the pres-
sure drop along the pulmonary capillaries is only a few cen-
timeters of water (similar to the pressure drop in systemic
capillaries), the pulmonary arterial and venous resistances
are low, so a relatively larger fraction of the total pulmo-
nary vascular resistance (35–45%) resides in the alveolar
capillaries at FRC.72,73 (For further information about pul-
monary circulation in health and disease see Chapters 6
and 83.)
Vasoactivity plays an important part in the local regu-
lation of blood flow in relation to ventilation.74,75 Because
smooth muscle surrounds the pulmonary vessels on both
* To convert from kPA to cm H2O, multiply by 10.3; to mm Hg, multiply
by 7.5.
10 PART 1 • Scientific Principles of Respiratory Medicine
A chovascular sheaths, interlobular septa). Extra-­
C the alveolar level. They are referred to as alveolar vessels in
A
A 5 µm
Figure 1.15 Alveolar capillaries are long. An alveolar capillary (C) is
shared longitudinally along its path across three alveoli (A). The alveolar
walls are flattened, and the wall junctions are sharply curved because the
lung is fixed in zone 1 conditions. Some red blood cells remain in the capil-
lary at an alveolar corner (arrow). (Perfusion-­fixed normal rat lung; airway
pressure = 30 cm H2O, pulmonary artery pressure = 25 cm H2O, left atrial
pressure = 6 cm H2O, scanning electron microscopy.)
the arterial and the venous side down to precapillary and
postcapillary vessels,76,77 any segment can contribute to
active vasomotion.78 In pathologic conditions, vascular
smooth muscle may extend down to the capillary level.79,80
Theoretically, gas exchange may take place through
the thin wall of almost any pulmonary vessel. At nor-
mal alveolar O2 tensions, however, little O2 and CO2 is
exchanged before the blood reaches the true capillaries.81
In the pulmonary arterioles, because of their small volume
(see Table 1.3), blood flow is rapid. As blood enters the vast
alveolar wall capillary network, its velocity slows, averag-
ing about 1000 μm/s (or 1 mm/s). Flow in the microcircu-
lation is pulsatile because of the low arterial resistance.82
Pulsations reach the microvascular bed from both the
arterial and the venous sides. In fact, one sign of severe
pulmonary hypertension is the disappearance of capillary
pulsations.83
The capillary network is long and crosses several alveoli
(Fig. 1.15) before coalescing into venules. The vast extent
of the capillary bed together with the length of the individ-
ual paths allows a transit time for RBCs sufficient for gas
exchange to take place. The estimate based on anatomy
of approximately 0.5-­to 1-­second average transit time is
essentially the same as that found using the carbon mon-
oxide diffusing capacity method, in which one divides
capillary blood volume by cardiac output to obtain mean
capillary transit time.84 In the normal lung, there is suffi-
cient time for equilibrium between the O2 and CO2 tensions
in the alveoli and the erythrocytes in the pulmonary cap-
illaries. Only under extreme stress (heavy exercise at low
inspired O2 tensions) or in severe restrictive lung disease are
the RBCs predicted to pass through the microcirculation
without enough time to reach diffusion equilibrium.85
Normally, capillary blood volume is equal to or greater
than stroke volume. Under normal resting conditions,
the volume of blood in the pulmonary capillaries is well
below its maximal capacity, however. Recruitment can
increase this volume by a factor of about three. Thus, the
normal capillary blood volume of 60 to 75 mL is one-­third
of the capacity (200 mL) measured by quantitative histol-
ogy.6 This reserve capacity of the capillaries allows them
to accommodate rapid increases in cardiac output during
times of high demand.
Anatomically, the pulmonary blood vessels can be divided
into two groups: extra-­alveolar and alveolar. Extra-­alveolar
vessels lie in the loose-­binding connective tissue (peribron-
alveolar
vessels extend into the TRUs. Alveolar vessels lie within the
alveolar walls and are embedded in the parenchymal con-
nective tissue. They are subject to whatever forces operate at
the sense that the effective hydrostatic pressure external to
them is alveolar pressure. Not all of the alveolar vessels are
capillaries, however. Small arterioles and venules, which
bulge into the air spaces, may also be affected by changes
in alveolar pressure. Likewise, not all of the capillary bed is
subjected to alveolar pressure under all conditions.86 The
corner capillaries in the alveolar wall junctions are protected
from the full effects of alveolar pressure by the curvature and
alveolar air-­liquid surface tension.87 This may account for
the fact that, even under conditions in which alveolar pres-
sure exceeds both arterial and venous pressure (“zone 1”),88
some blood continues to flow through the lung.89 One has to
go several centimeters up into zone 1 before blood flow stops
completely. (For a discussion of distribution of pulmonary
blood flow and lung zones, see Chapter 10.)
An important question is whether the normal human
lung contains connections between the pulmonary arter-
ies and veins that permit some portion of pulmonary blood
flow to bypass the capillary network. Whereas such vessels
may develop congenitally or pathologically,90 function-
ing short circuits probably do not exist in the normal lung.
(Pathologic arteriovenous communications are discussed
in Chapter 88.)
In addition to its function in gas exchange, the pulmo-
nary circulation is involved in a number of other func-
tions important to homeostasis. The pulmonary vascular
bed serves as a capacitance reservoir between the right
and left sides of the heart. Consequently, the reservoir of
blood in the pulmonary circulation is sufficient to buffer
changes in right ventricular output for two to three heart-
beats. The pulmonary vascular bed also serves as a filter,
trapping embolic material and preventing it from reaching
systemic vascular beds. For example, during intravascular
coagulation or in processes involving platelet or neutro-
phil aggregation, the predominant site of sequestration is
the lung. The main anatomic reason for this is that 75% of
the total circulating blood volume is in the venous circuit,
and the lung’s microvascular bed is the first set of small ves-
sels through which the blood flows. Moderate numbers of
microemboli generally produce no detectable dysfunction
in the lung because of the huge array of parallel pathways
in the pulmonary microcirculation. At most, microemboli
temporarily block flow to a portion of or to an entire TRU.
The fate of such emboli is not clear. Some are phagocytosed
and removed into the lung tissue.91 Some emboli can be
degraded to a small size, pass through into the systemic cir-
culation, and be removed by the reticuloendothelial system.
The filtering function of the lung enables such clinical stud-
ies as the perfusion scan, in which macroaggregated albu-
min is trapped by the lung vessels as a measure of perfusion.
(Further information about the pathophysiology of throm-
boembolic disorders is presented in Chapter 81.)

1 1
A oli.92–95 Alas, the term acinus also has been used to describe
E lus: the TRU. The physiologists’ alveolus is the TRU because
COL * the unit’s definition is functional.
Nu
R
C E
1 output. However, most disorders of oxygenation are due to
EL
A
1
1.0 µm
Figure 1.16 Cross-­section of an alveolar wall showing the path for
oxygen and carbon dioxide diffusion. The thin side of the alveolar wall
barrier (short double-­headed arrow) consists of type 1 epithelium (1), inter-
stitium (asterisk) formed by the fused basal laminae of the epithelial and
endothelial cells, capillary endothelium (E), plasma in the alveolar capillary
(C), and finally the cytoplasm of the red blood cell (R). The thick side of
the gas-­exchange barrier (long double-­headed arrow) has an accumulation
of elastin (EL), collagen (COL), and matrix that jointly separate the alveo-
lar epithelium from the alveolar capillary endothelium. As long as the red
blood cells are flowing, oxygen and carbon dioxide probably diffuse across
both sides of the air-­blood barrier. (See also Video 3.1 for a three-dimen-
sional ultrastructural view of alveolar walls.) A, alveolus; Nu, nucleus of the
capillary endothelial cell. (Human lung surgical specimen, transmission
electron microscopy.)
TERMINAL RESPIRATORY UNITS
The TRU consists of a respiratory bronchiole and all the
alveolar ducts together with their accompanying alveolar
ducts and alveoli (see Fig. 1.14; see Table 1.2). The TRU has
both a structural and a functional existence and was first
described in the human lung by Hayek.11 In the human
lung, this unit contains approximately 100 alveolar ducts
and 2000 alveoli. At FRC, the unit is approximately 5 mm
in diameter, with a volume of 0.02 mL. There are about
150,000 such units in the lungs of normal adult humans.6
The functional definition of the TRU is physiologic;
namely, gas-­phase diffusion is so rapid along patent air-
ways that the partial pressures of O2 and CO2 are uniform
throughout the unit.28 Therefore, physiologically, O2 in the
gas phase anywhere along the TRU will diffuse along its
concentration gradient across the extremely thin walls into
RBCs flowing in the capillaries (Fig. 1.16), where O2 com-
bines with hemoglobin. CO2 diffuses in the opposite direc-
tion along its concentration gradient. A key point about
diffusion is that the process is much faster in the gas phase
than in the liquid phase. Thus, the TRU size is defined in
part by the fact that gas molecules can diffuse and equili-
brate anywhere within the unit more rapidly than they can
diffuse across the air-­blood barrier into the blood. Of note,
the solubility of O2 in water is low relative to its concentra-
tion in gas. CO2 is much more soluble in water (20 times the
solubility of O2 in water), and therefore CO2 diffuses rapidly
into the gas phase, even though the driving pressure for CO2
diffusion is only one-­tenth that for O2 entering the blood.
A source of confusion is the term acinus in the context of
the lung. Historically, the term acinus has been defined dif-
ferently by different fields. In pathology, the acinus is bigger
than a TRU. The pathologists’ acinus consists of a terminal
bronchiole and all of the subsequent respiratory bronchioles
1 • Anatomy 11
together with their accompanying alveolar ducts and alve-
the TRU unit.96 This chapter uses the physiologists’ alveo-
In general, O2 diffusion is not limiting in the normal lung,
except during heavy exercise while breathing gas containing
very low O2 concentrations (e.g., at high altitudes).85 Even at
that, it is not so much diffusion that is limiting, but the fact that
the transit time of the RBCs is reduced due to increased cardiac
ventilation-­perfusion inequalities97 (see also Chapter 44).
All portions of the TRU participate in volume changes
with breathing.98,99 When a unit increases its volume
from FRC, the alveolar gas that had been in the alveolar
duct system enters the expanding alveoli, together with a
small portion of the fresh air. Most of the fresh air remains
in the alveolar duct system. This does not lead to any sig-
nificant gradient of alveolar O2 and CO2 partial pressures
because diffusion in the gas phase is so rapid that there is
equilibrium within a few milliseconds. However, nondiffus-
ible (suspended or particulate) matter remains away from
the alveolar walls and is expelled in the subsequent expira-
tion.100 This explains why it is difficult to deposit aerosols
on the alveolar walls and why large inspired volumes and
breath-­holding are needed for efficient alveolar deposition.
The anatomic alveolus is not spherical (Fig. 1.17, see Fig.
1.15). It is a complex geometric structure with flat walls
and sharp curvature at the junctions between adjacent
walls. The most stable configuration is for three alveolar
walls to join together, as in foams.6 The resting volume of
an alveolus is at 10–14% of TLC. When alveoli go below
their resting volume, they must fold up because their walls
have a finite mass (see Fig. 1.17). Most of the work required
to inflate the normal lung is expended across the air-­liquid
interface to overcome surface tension; the importance of
the air-­liquid interface is demonstrated by the low pressure
required to “inflate” a liquid-­filled lung with more liquid101
(see Fig. 3.5 and Chapter 3).
The phenomenon of TRU, or alveolar, stability is complex
because not only is air-­liquid interfacial tension involved
but each flat alveolar wall is part of two alveoli, and both
must participate in any volume change. Therefore atelec-
tasis does not usually involve individual alveoli but rather
relatively large units (Fig. 1.18).102
The alveolar walls are composed predominantly of pul-
monary capillaries. In the congested alveolar wall the blood
volume may be greater than 75% of the total wall volume.
Alveoli near the top of the lung show less filling of the capil-
laries than those at the bottom.103,104 This affects regional
diffusing capacity, which is dependent on the volume of
RBCs in the capillaries.
The transition from a cuboidal epithelium of the respira-
tory bronchiole to the squamous epithelium of the alveolus
is abrupt (Fig. 1.19). Little is known about the function, if
any, of this transitional junction. Although Macklin105
speculated that the permeability of the bronchiole-­alveolar
epithelial junctions might be unique, no definitive differ-
ence has been demonstrated.106 The controversy continues
as to whether this region shows unique permeability fea-
tures that might participate in clearance of particles or leak-
age of edema.107–109
12 PART 1 • Scientific Principles of Respiratory Medicine

AI AI
Figure 1.17 Alveolar shape changes at rep-
resentative points along the air deflation
pressure-­ volume curve of the lung. The
four micrographs are at the same magnifica-
tion. The air deflation pressure points are as
follows: (A) airway pressure = 30 cm H2O (total
lung capacity [TLC]); (B) 8 cm H2O (≈50% TLC);
(C) 4 cm H2O (near functional residual capacity A 20 µm B 20 µm
[FRC]); and (D) 0 cm H2O (minimal volume). Vas-
cular pressures are constant (pulmonary artery
presssure = 25 cm H2O and left atrial pressure
= 6 cm H2O). Intrinsic alveolar shape (AI) is
maintained from TLC to FRC (A–C). The alveo-
lar walls are flat, and there is sharp curvature at
the junctions between adjacent walls. Note the AI
flat shape of the alveolar capillaries (arrow) at
TLC ([A] lung zone 1 conditions) compared to
their round shape (arrow) at FRC ([C] lung zone
3 conditions). The alveolar walls are folded and
alveolar shape is distorted at minimal lung vol-
ume (D). The arrow in (B) identifies an alveolar AI
type 2 cell at an alveolar corner. The arrowhead
in (B) identifies a pore of Kohn. (Perfusion-­fixed
normal rat lungs, scanning electron micros- C D
copy.) 20 µm 20 µm

AD RB
Ci
AM
E

SM
500 µm
5 m

Figure 1.18 Histologic appearance of atelectasis. Atelectasis usually
involves relatively large units of lung parenchyma, rather than individual
alveoli. Alveolar walls in the atelectatic units are folded, distorting alveolar
air space and capillary shape, as shown in Fig. 1.17D. (Sheep lung injured
by air emboli, 2 μm–thick glycol methacrylate section, light microscopy.)
Trapping and clearance of particulate matter imping-
ing on the alveolar surfaces is vital and takes place in the
alveolar surface liquid. Within this liquid are suspended
alveolar macrophages (see Fig. 1.19).110 The majority of
alveolar macrophages that reach the terminal airways via
the slow, upward flow of alveolar lining liquid are expelled
with the surface film as it is pulled up onto the mucociliary
escalator.111,112
LYMPHATICS
Another route for clearance of particulate matter and fluid
from the lung is the pulmonary lymphatic system (see
Figure 1.19 The respiratory bronchiole (RB)–alveolar duct (AD) junc-
tion is abrupt. The junction is demarcated by an abrupt transition (arrow-
head) from low cuboidal epithelial cells (E) with cilia to squamous epithelial
cells. Submerged in the lining liquid (arrow) are an alveolar macrophage
(AM) and cilia (Ci). Airway smooth muscle cells (SM) extend to this level
of the airway tree. (Human lung surgical specimen, transmission electron
microscopy.)
Chapter 7). Lymphatics of the lung are subdivided into two
principal groups based on their location: a deep plexus and
a superficial plexus.11,58,113,114 Both plexuses are made up
of initial and collecting lymphatics, with communications
between the two.11,58,108,113 The deep plexus is situated in the
peribronchovascular connective tissue sheaths of the lung
(see Fig. 1.1).11,58,108,113 Lymphatics in the deep plexus are
distributed around the airways, extending peripherally to
the respiratory bronchioles and next to branches of the pul-
monary arteries and veins.11,58,108,113 Lymphatics are not
found in the alveolar walls. The superficial plexus is located
in the connective tissue of the visceral pleura. This plexus is

A
1
UA
E L 0.5 µm
Figure 1.20 Ultrastructure of unmyelinated axons in the lung paren-
chyma. Unmyelinated axons (UA), known as C fibers, are shown situated
in the interstitium of a respiratory bronchiole, between an alveolar type 1
cell (white 1) lining an alveolus (A) and an initial lymphatic (L). Although the
presence of small clear vesicles is suggestive of cholinergic (autonomic)
axons, unequivocal identification as either motor or sensory fibers is not
possible in random thin sections. E, lymphatic endothelial cell. (Human
lung surgical specimen, transmission electron microscopy.)
prominent in the lung of species with thick visceral pleura,
including human lung (see the section “Pleural Space
and Pleural Membranes”).11,58,113 Collecting lymphatics
have one-­way valves and in large species, such as humans
and sheep, a discontinuous, thin layer of smooth muscle.
Of note, the visceral pleural lymphatics do not open into
the pleural space and do not participate in pleural liquid
clearance.
Lymph is propelled centripetally toward the lung’s hilum
or pulmonary ligament by movements of the lungs through
the respiratory cycle and by heart pulsations, to reach
regional lymph nodes. In the human, pulmonary lymph
flows to extrapulmonary lymph nodes located around the
primary bronchi and trachea.11,58,113
INNERVATION
Innervation of the human lung consists of sensory (afferent)
and motor (efferent) pathways.92,113,115,116 Fibers of the sen-
sory pathway include myelinated, slowly adapting stretch
receptors (Hering-­Breuer reflex) and irritant receptors, but
most sensory fibers are unmyelinated, slow-­conducting C
fibers located in the TRUs, either along the bronchioles or
within the alveolar walls (Fig. 1.20). Investigators have
speculated about the function of C fibers since Paintal first
suggested that they played a role in sensing parenchymal
connective tissue distortion, as during pulmonary vascular
congestion and interstitial edema.117–120 The speculation
has neither been proven nor disproven.
The motor pathways reach the lung through the sympa-
thetic and parasympathetic nervous systems. Preganglionic
contributions to the sympathetic nerves arise from the
upper four or five thoracic paravertebral ganglia, whereas
the preganglionic parasympathetic nerves originate in the
brainstem motor nuclei associated with the vagus nerves.
Postganglionic sympathetic nerve fibers terminate near air-
ways, vascular smooth muscle cells, or submucosal glands.
Postganglionic parasympathetic fibers extend from ganglia
mainly located external to the smooth muscle and cartilage.
1 • Anatomy 13
Chest
Wall
Lung
25 µm
Figure 1.21 The pleural space is a real space. The dark band delimited
by the opposed arrows is the pleural space, which is located between the
chest wall and lung. (Frozen sheep chest wall and lung, unstained.)
Some submucosal ganglia exist, but they are generally
smaller and have fewer neurons.
PLEURAL SPACE AND PLEURAL
MEMBRANES
As stated earlier, the primary function of the lung is ensur-
ing efficient gas exchange between alveolar air and alveolar
capillary blood. This vital function is met, in part, by exten-
sive and rapid movement of the lung within the pleural
space and its pleural liquid.121,122 Online supplemental digi-
tal videos linked to this chapter provide a glimpse of the view
that surgeons have during dissection through the intercos-
tal muscles: The lungs glide along the deep surface of the
translucent endothoracic fascia and parietal pleura (see
Videos 1.1 to 1.5). The pleural space also serves as an out-
let into which pulmonary edema liquid can escape.123,124
The pleural liquid also serves to couple the lung to the chest
wall.125 What are the anatomic features of the pleural space
and pleurae that contribute to these functions?
An important anatomic fact is that the pleural space is
a real space (Fig. 1.21); it is not a potential space.3,125 The
pleural space surrounds the lung, except at its hilum, where
the parietal pleura and visceral pleura join.11,91 Separations
are present between the parietal and visceral pleurae along
the interlobar fissures and costodiaphragmatic recesses.
The normal volume of pleural liquid is 0.1 to 0.2 mL/kg
body weight in most mammals.125,126 This volume is dis-
tributed across a pleural surface area of approximately
1000 cm2/lung and pleural space width of 10 to 20 μm (see
Fig. 1.21).3,125 Normally, there is little or no contact across
the pleural space because the microvilli that extend from
the parietal and visceral mesothelial cells are only 3 to 5 μm
long.2,3,127,128
The unique anatomic features of the parietal pleura are
the lymphatic stomata.128–133 The lymphatic stomata are
openings (≈1–12 μm in diameter) between parietal and
mesothelial cells (Fig. 1.22), which are continuous with
14 PART 1 • Scientific Principles of Respiratory Medicine
s space are cleared almost entirely by the parietal pleural
s
s these regards, normal pleural liquid is cleared by mecha-
A 4 µm
s and goblet cells, as well as some club cells and a small num-
4 µm
B varies along the proximal-­to-­distal axis, with a decreasing
Rib
L way epithelium because these cells are able to self-­renew
50 µm
C
Figure 1.22 Surface view of lymphatics stomata, initial lymphatics,
and collecting lymphatics of the parietal pleura. (A–B) Scanning elec-
tron micrographs that show the unique structure of lymphatic stomata (S).
Stomata are apertures between the pleural space and the initial lymphat-
ics in the parietal pleura. Three stomata are visible in a low-­magnification
field of view in (A). Stomata are located over intercostal muscles. (B) shows
a different stoma at a higher magnification. Microvilli are not present at
the aperture of the stomata, which are lined by mesothelial cells. (Sheep
parietal pleura, scanning electron microscopy.) (C) shows a portion of the
parietal pleura, where colloidal carbon is seen in four beds of initial lym-
phatics (arrows) located over an intercostal space. Colloidal carbon is also
in collecting lymphatics (L) that cross a rib, where the collecting lymphat-
ics drain into lymphatic vessels that accompany the intercostal vessels.
(Rabbit, macroscopic view of the parietal pleural after colloidal carbon was
placed in the pleural space in situ.)
the lumen of lymphatic capillaries. The size likely varies
as the chest moves with ventilation. Tracer studies reveal
that India ink and chicken RBCs (which are nucleated and
therefore easily identifiable) are cleared almost exclusively
from the pleural space by the stomata, which are located
over the intercostal spaces in the distal half of the thorax,
and along the sternum and pericardium of experimental
animals that have been studied.128,134 Physiologic studies
showed that protein and particulate matter in the pleural
system of stomata and lymphatics.129,135 The lymphatics
transport the cleared pleural liquid (lymph) to regional
lymph nodes along the sternum and vertebral column and
then, to the thoracic duct and right lymphatic duct. In
nisms consistent with normal interstitial liquid turnover in
the peritoneum.
CELLULAR ANATOMY OF THE
LUNG
AIRWAY LINING CELLS
The airway epithelium of the human proximal conducting
airways contains different types of epithelial cells with spe-
cific functions. These cells include basal cells, ciliated cells,
ber of brush cells, single neuroendocrine cells,136–139 and
ionocytes.140,141 Submucosal gland epithelium, contiguous
to the airway surface epithelium, contains serous and gob-
let secretory cells.142 The proportion of the different epithe-
lial cell types that form the healthy adult human airways
number of submucosal glands and an increasing number of
club secretory cells.137,143
Basal cells function as progenitor cells within the air-
or differentiate into secretory, goblet, and ciliated cells in
homeostasis and during injury repair144,145 (see Chapter
8). In humans, basal cells cover most of the airway base-
ment membrane146; however, they do not reach the air-
way lumen and thereby contribute to the pseudostratified
appearance of the airway epithelium. These cells interact
with columnar epithelium, basement membrane, and
underlying mesenchymal cells, inflammatory cells, lym-
phocytes, and dendritic cells.147,148
Ciliated cells protect the TRUs by filtering the inhaled
air for solid particles and removing them by mucocili-
ary clearance. Nearly half of the epithelial cells in the
normal human airway are ciliated at all airway genera-
tions (Fig. 1.23), down to bronchioles (see Fig. 1.19).149
Each ciliated cell has multiple cilia (≈200 cilia) that have
a specialized capping clawlike structure called a ciliary
crown, to make the distal portion stiff to propel the liq-
uid lining layer along the airways and to promote debris
clearance from the airways. The cilia have structural
and motor proteins that produce coordinated and direc-
tional beating at 8 to 15 Hz, which is critical for muco-
ciliary clearance.136–138,150 As the airway superficial
lining liquid moves centripetally, it encounters larger
and fewer airways, which have a smaller total perim-
eter. For example, the total perimeter of approximately
150,000 terminal bronchioles is much greater than the
total perimeter of the five lobar bronchi.6 If the lining liq-
uid volume remained constant, the liquid layer ought to
grow in thickness, but this does not happen, suggesting
that much of the liquid is reabsorbed during its ascent
along the airways.

C S
BV
10 µm
Figure 1.23 Structure of bronchial mucosa. The bronchial mucosa
consists of pseudostratified, columnar epithelium with cilia (C) and gob-
let cells (red arrow). The cilia, which form a thick carpet, move rhythmi-
cally and thereby propel liquid, mucus, cells, and debris centrally toward
the pharynx. The dark band immediately beneath the cilia (black arrow) is
produced by the basal bodies. By transmission electron microscopy, basal
bodies are recognized as modified centrioles. A lymphocyte (white arrow-
head) is intercalated among the epithelial cells. A bronchial blood vessel
(BV) is located beneath the mucosal layer. (Human lung surgical specimen,
10 μm–thick paraffin section, light microscopy.)
CL
CE
CL
L stances that help protect the lungs from particles and infec-
NEC 1.0 µm
Figure 1.24 Cellular structure of terminal airway epithelium. The epi-
thelium consists mainly of ciliated epithelium (CE) and nonciliated club
cells (CL). Club cells have the ultrastructural features of secretory cells;
namely, they possess basally located rough endoplasmic reticulum, peri-
nuclear Golgi apparatus, apically located smooth endoplasmic reticulum,
and prominent membrane-­bound granules (arrowheads). A lymphocyte (L)
is intercalated among the epithelial cells. A small portion of a neuroendo-
crine cell (NEC) containing characteristic dense-­cored vesicles is also visible
at the base of the epithelial cells. (Human lung surgical specimen, transmis-
sion electron microscopy.)
Goblet cells are secretory cells that produce and store
mucus in granules of about 800 nm diameter. Secretion of
the correct amount of mucus with an optimum viscoelastic
profile is essential for maintenance of normal mucociliary
1 • Anatomy 15
M
20 µm
Figure 1.25 Structure of submucosal glands. This figure provides a
higher magnification view of a region shown in Fig. 1.7. The mixed, com-
pound tubuloacinar glands contain mucus-­secreting cells (M) and serous-­
secreting cells (S). The latter type form crescentic caps, or demilunes, over
the ends of the acini, the rounded secretory units of the gland. Mucous
cells are the predominant glandular cell type. (Human lung surgical speci-
men, right middle lobar bronchus, 2 μm–thick glycol methacrylate section,
light microscopy.)
clearance.137,151 Goblet cells also secrete inflammatory
mediators that participate in the recruitment and activa-
tion of immune cells. Goblet cells are found on the airway
surface and in the submucosal glands.11,58 Furthermore,
goblet cells are capable of division and may show stem cell
multipotency.152
Club cells153 are dome-­shaped cells with dense cytoplas-
mic granules and microvilli that, in humans, are restricted
to terminal and respiratory bronchioles,154,155 where club
cells serve as facultative progenitors for themselves and
for ciliated epithelial cells, and they maintain the nor-
mal epithelium of the distal conducting airways (see Fig.
1.24).154,156 Single-­cell transcriptome analyses have sug-
gested novel roles for club cells in host defense, antiprote-
ase activity, and physical barrier function.157 Club cells also
secrete secretoglobin 1A1; surfactant proteins A, B, and D;
and lipids.156,158,159
Submucosal gland epithelial cells line the submucosal glands
(Fig. 1.25), which are continuous with the airway epithelium
and are located below the airway luminal surface of all of the
cartilaginous proximal airways. Submucosal gland epithelial
cells secrete mucins, water and electrolytes, and other sub-
tious agents. Studies of the regulation of secretion in vivo
and in vitro show that secretion is modulated by neurotrans-
mitters, including cholinergic, adrenergic, and peptidergic
transmitters,42 and by inflammatory mediators, such as
histamine,43 platelet-­activating factor,44 and eicosanoids.45
Submucosal glands are connected to the airway surface by a
duct lined by epithelial cells identified as ductal cells.160 The
submucosal gland epithelium contains goblet cells (described
earlier) and serous cells. Serous cells are the defensive cells of
the mucosa because they secrete innate immunity proteins,
such as lysozyme, SPLUNC1, β-­defensins,161 mucins, and
electrolytes, including chloride and bicarbonate, to control
the fluidity of the mucus. These cells, in contrast to goblet
cells, have discrete electron-­dense granules of about 600 nm
diameter. A few serous cells are also present in the surface
epithelium of the human bronchioles.162
Rare lung epithelial cell types include pulmonary neuro-
endocrine cells, ionocytes, and brush (tuft) cells. These cell
16 PART 1 • Scientific Principles of Respiratory Medicine
NEB
1.0 µm
Figure 1.26 Neuroepithelial body (NEB) located in a peripheral air-
way. Neuroepithelial bodies contain aggregates of neuroendocrine cells.
A characteristic ultrastructural feature of neuroendocrine cells is the pres-
ence of small (0.1–0.3 μm in diameter) dense-­cored vesicles in their cyto-
plasm (arrow). Each dense-­cored vesicle is bounded by a unit membrane.
(Human lung surgical specimen, transmission electron microscopy.)
types are continually and directly replenished by basal pro-
genitor cells.
Pulmonary neuroendocrine cells serve as O2 sensors163,164
and release hormones that affect smooth muscle (e.g., vaso-
active intestinal peptide165,166 and substance P).167–170
Pulmonary neuroendocrine cells represent less than 1% of
airway epithelial cells and are a component of the diffuse
neuroendocrine system called the amine uptake and decar-
boxylation system.171,172 This system is composed of single
neuroendocrine cells and clusters of such cells, known as
neuroepithelial bodies,173 distributed along the airway epi-
thelium down to the region of alveolar ducts.174–177 The
neuroepithelial bodies are preferentially located at airway
bifurcations. Pulmonary neuroendocrine cells are ultra-
structurally characterized by dense-­cored vesicles in their
cytoplasm (Fig. 1.26). The dense-­cored vesicles are the stor-
age sites of amine hormones (serotonin, dopamine, norepi-
nephrine) and peptide hormones (bombesin, calcitonin,
leu-­enkephalin).166 Neurons are also associated with neu-
roendocrine cells.
Ionocytes are a recently identified and rare cell popula-
tion that serves as the primary source of cystic fibrosis
transmembrane conductance regulator activity in the con-
ducting airway epithelium in mice and humans.140,141 The
cystic fibrosis transmembrane conductance regulator is a
membrane protein that conducts chloride ions and water
across epithelial cell membranes. Mutations in this gene
cause cystic fibrosis (see Chapters 67 and 68).
Brush (tuft) cells are pear-­shaped cells, with a narrow
apex from which extend a tuft of blunt, squat microvilli
that stretch their filaments into the underlying cytoplasm.
Brush cells also contain numerous intracytoplasmic
membrane-­bound inclusions and seem to have a chemo-
sensory role, although their function has not been clearly
defined.178
The complex and diverse cellular composition of the
airway epithelium in mammalian organisms has evolved
to support the main functions of the airways, namely
to connect the outside world to the TRUs, to maintain
a balanced secretion and absorption of electrolytes and
water from the lining liquid, and to facilitate mucociliary
clearance.
M
A
C
E
IC
2 5 µm
Figure 1.27 Cells of the terminal respiratory unit. An alveolar macro-
phage (M) is located in an alveolus (A). Alveolar macrophages are the air
space scavengers that are cleared either up the mucociliary escalator or
into the interstitium. These cells can be activated to express and secrete
cytokines, which may interact with other cells. Cells of the alveolar wall
are the lining alveolar type 1 and 2 cells (1 and 2, respectively) and the
enclosed capillary (C), endothelial cells (E), and interstitial cells (IC; fibro-
blasts). (Human lung surgical specimen, transmission electron microscopy.)
ALVEOLAR LINING CELLS
The alveolar epithelial cells that line the anatomic alveoli
include alveolar type 1 (AT1) and alveolar type 2 (AT2) cells
and a minor subpopulation of alveolar epithelial progenitors
(AEPs), all supported by a shared basal membrane and the
subjacent capillaries and fibroblasts.179,180 AT2 cells out-
number AT1 cells (≈15% vs. 8–10% of total peripheral lung
cells, respectively). However, AT1 cells account for approxi-
mately 90–95% of the alveolar surface area of the periph-
eral lung.181 (See also Video 3.1 for a three-dimensional
ultrastructural view of AT1 cells.)
AT1 cells have extensive, attenuated cytoplasmic pro-
cesses that form a large, thin surface area for gas exchange
(Figs. 1.27 and 1.28). AT1 cells express water chan-
nels182 and also epithelial sodium channels and membrane
sodium-­potassium–adenosine triphosphatase,183,184 which
play a role in pulmonary water flux.185 Adult rodent and
human AT1 cells have a limited proliferative capacity and
are sensitive to injury. Under normal conditions, AT1 cells
attach via tight junctions to neighboring AT2 cells to form a
relatively impermeable seal between alveolar air and alveo-
lar wall interstitial spaces. AT1 cells contain many small,
non–clathrin-­coated vesicles, or caveolae, that are open
either to the alveolar lumen or interstitium or are detached
from the surface as free vesicles in the cytoplasm.186 The
vesicles contain caveolin-­1 protein, a scaffolding protein
that organizes specialized membrane phospholipids and
proteins into vesicles. Caveolin-­1 can bind free cholesterol
and modulate the efflux of cholesterol from the cell when
intracellular concentrations rise.187,188 Caveolae appear to
sequester various proteins into the vesicles, such proteins
that include growth factor receptors, signaling molecules
such as G proteins, calcium ion receptors, and pumps.
AT2 cells are small (≈300 μm3) cuboidal cells with short
stubby apical microvilli (see Figs. 1.27 and 1.29). AT2 cells
are specialized in the production and recycling of proteins
and phospholipids that form surfactant. Surfactant is stored
in cytoplasmic lamellar bodies, which are membrane-­bound
inclusions (diameter from <0.1–2.5 μm) that are stacked
layers of cell membrane-­like material (Fig. 1.29) composed
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Edeldenkende den Verunglückten bemitleiden und dem
gewissenlosen Urheber zürnen. Jetzt dagegen sieht man beim
ersten flüchtigen Blick bloß eine Reihe Vorfälle, die man lächerlich
findet. Man vergißt aber die Lüge und den sündhaften Leichtsinn,
welche der ganzen Sache zugrunde liegen, ja ohne es zu merken
lacht man auch über sie — über eine Sünde.
Ich habe aber noch eine andere Frage. Angenommen, der
schiefe Philipp brächte es fertig, den Professor in ganz ähnliche,
aber völlig ungefährliche Lagen zu bringen. Wäre er dann von aller
Schuld freizusprechen?“
Einige Antworten lauteten bejahend, andere zweifelnd. Percy
Wynn verneinte es.
„Aber warum nicht?“
Das wußte auch Percy nicht zu sagen.
„Gut, ich will Euch helfen. Ihr kennt das vierte Gebot. Whyte, wer
hat aber an der Ehre und Liebe, die wir den Eltern schulden, Anteil?“
„Die Lehrer und alle, welche die Stelle der Eltern vertreten, auch
die geistliche und die weltliche Obrigkeit.“
Jetzt blitzte es auf mehreren Gesichtern.
„Nun? — Hodder!“
„Es war auch deshalb sündhaft, weil Philipp seinen Lehrer
verspottete. Denn der Professor hatte ein Recht auf die Ehre all
seiner Schüler, den schiefen Philipp nicht ausgenommen.“
„Aber Du hast doch wohl gehört, daß der Professor so schlecht
sprach und überhaupt manche Sonderbarkeiten an sich hatte.“
„Das ist kein Grund, ihm die Ehre zu versagen; denn er bleibt
doch immer noch der Stellvertreter der Eltern, den man ehren muß.“
„Sehr gut, Hodder. Man würde es ja nicht tadeln, wenn der
schiefe Philipp einen Gleichgestellten etwas hänselte. Allein dem
Lehrer gegenüber ist dies eine kränkende Beschimpfung, um so
kränkender, da Philipp auch seine Mitschüler zu der gleichen Roheit
und Sünde verleitet.
 Jetzt seht Ihr die Doppelsünde, die hier unter den heiteren
Blumen von Fröhlichkeit und Scherz verborgen liegt. Wehe dem
Leser, der ihr geheimes Gift nicht erkennt. Langsam, unmerklich,
aber ganz sicher wird es wirken. Ohne sich bewußt zu werden wird
der Leser nach und nach Lüge, Verachtung der Vorgesetzten und
bodenlosen Leichtsinn als gut, ja als witzig und heldenhaft
betrachten, wenn es ihn nur zum Lachen reizt. Zwar kommt das
Verderben nicht gerade immer mit einem einzigen Buche, obgleich
es nicht an solchen fehlt, deren einmaliges Lesen unschuldige
Herzen für immer verdorben hat. Manche töten nicht so schnell. Bei
Zeiten gewarnt, kann sich ein Knabe durch Folgsamkeit ihrer bösen
Wirkung entziehen. Allein einer fortgesetzten Lektüre solcher Bücher
wird auch die stärkste Tugend auf die Dauer nicht widerstehen.
Noch eines wird Euch jetzt klar geworden sein, daß es nämlich
oft einer bedeutenden Reife des Geistes, einer großen
Selbständigkeit bedarf, um das Verderbliche eines Buches mit
Sicherheit zu entdecken.“
Pater Middletons Worte waren von durchschlagender Wirkung.
Mehrere seiner Schüler, die sich bis dahin heimlich der Lektüre von
anrüchigen Zehn-Cent-Geschichten hingegeben, wandten sich mit
Abscheu von denselben weg. In die ganze Klasse fuhr ein Eifer für
gute Bücher und für Verbreitung derselben unter den Mitzöglingen.
Percy erwarb sich hierbei eigentliche Verdienste. Wie Kenny besaß
er eine weit ausgedehnte Belesenheit, hatte jedoch das Glück
gehabt, daß eine umsichtige, fromme und gebildete Mutter seine
Bücher aufs sorgfältigste auswählte. Zugleich hatte ein vortrefflicher
Privatlehrer durch gediegene Unterweisung seinen Geschmack und
sein Urteil zu einer frühen Reife geführt, so daß er mit größerer
Sicherheit das Gute und Edle vom Minderwertigen und Verwerflichen
unterschied.
Unterdessen verwandelt sich unser Freund immer mehr in einen
rechten Jungen. Fester und frischer blicken die blauen Augen aus
dem unschuldigen Antlitz, das, noch ebenso anmutig und edel wie
beim Beginne des Schuljahres, jetzt auch in der Rosenfarbe
blühender Gesundheit prangt. Seine ganze Erscheinung ist voller
und stärker geworden. Die viele Bewegung in frischer, freier Luft hat
ihn gekräftigt und kräftigt ihn noch. Und seine Hände! ah, Tom
Playfair wird sich wohl bedenken, ihn noch einmal auf seinen Arm
schlagen zu lassen.
Ruhig verflossen noch die Wochen bis Weihnachten. Allein
dieses Fest sollte nicht ohne besondere Ereignisse vorübergehen,
Ereignisse, die Percys Entwickelung wesentlich fördern halfen.
Wir haben gesehen, wie Percy das Allermädchenhafteste, das er
nach Maurach mitbrachte, schnell abstreifte. Er hat den Beweis
geliefert, daß er Großmut und Opfersinn in mehr als hinreichendem
Maße besitzt, um den Anforderungen, die das Leben an den
Christen stellt, vollauf zu entsprechen. Allein seine Nächstenliebe
erscheint doch noch mehr als eine rein persönliche: den Freunden,
die ihm wohlgethan, gilt in Dankbarkeit seine heldenmütige That.
Sein Gesichtskreis muß sich erweitern. Die Religion, in deren
Schoße er erzogen ist, auf deren geheiligtem Boden all seine
Grundsätze und Anschauungen wurzeln, hat ihn schon mit der
geistigen Sehkraft begabt, welche genügt, um eine Welt zu
umspannen, und die sich entfalten wird, sobald sich die Gelegenheit
dafür bietet.
 23. Kapitel.
Auf der Gasse.
n einem hellen Dezembernachmittag sehen wir drei Zöglinge
des Pensionates den Weg zur Stadt antreten. Munter
schreiten sie dem kalten Winde entgegen, der bald ihre
Wangen mit einer dunklen Röte bedeckt.
„Nur noch acht Tage!“ sagt Donnel.
„Jawohl,“ erwidert Keenan, „und dann eine ganze Woche Spaß!
— Diese Nacht wird es wohl gehörig frieren; es ist jetzt schon so
kalt, wie noch nie im ganzen Winter.“
„O, ich hoffe, daß es tüchtig friert!“ sprach Percy, der dritte in dem
fröhlichen Bunde. „Meine Schlittschuhe sind gestern angekommen,
und ich möchte so gern probieren, wie eigentlich das
Schlittschuhlaufen geht.“
„Was?“ fragten beide erstaunt, „Du kannst nicht Schlittschuh
laufen?“
„Nein,“ antwortete Percy lächelnd; „ich durfte noch nicht mitgehen
aufs Eis.“
„Unbegreiflich!“ sprach Keenan. „Ich sehe nicht ein, was ein
Junge im Winter anfangen soll, wenn er nicht Schlittschuh laufen
kann. Aber tröste Dich, wir wollen Dir nachhelfen.“
 „Ich muß gestehen, daß der Winter bis jetzt in der That meine
Vorliebe nicht besessen hat.“
„Kein Wunder!“ lachte Donnel. „Wer nicht einmal Schneebälle
drehen, geschweige denn damit werfen kann, wer weder
Schlittschuh läuft noch Schlitten fährt, wer sich vor jeder
Schneeflocke fürchtet, was kann der vom Winter zu erwarten
haben? Ich für meinen Teil ziehe den Winter dem Sommer bei
weitem vor.“
„Wirklich? das hätte ich nicht für möglich gehalten.“
„Und ich thu’ das auch,“ versicherte Keenan.
„Gieb mir den Winter, laß schneien knietief!
Wecke den Nordwind, den kalten, der schlief!
Es decke der See sich mit blankem Kristall!

Und dann ein noch blankeres Paar Schlittschuhe! Hurra! Dann

fliegen wir, daß der Wind in den Haaren zischt, über die tönende
Bahn! Das nenne ich Spaß!“
„Und ich,“ nahm Donnel das Wort, „ich wünsche mir eine
Schlittenbahn, glatt wie aus Diamant und hoch wie ein Berg, mit
einem Handschlitten vom besten Stahl. Dann sollte es
hinuntergehen, daß jedem, der es sieht, das Blut erstarren möchte,
und daß ich wie der Blitz noch dahinschieße, soweit man sehen
kann. — Ich vergesse auch nie, wie ich einmal mit meinem Vater
eine längere Schlittenpartie machte. Besonders zur Nachtzeit war es
unbeschreiblich schön. Die Sterne flimmerten und funkelten so hell
wie nie im Sommer, der Mond goß ein feenhaftes Licht über die
schneeschimmernde Landschaft, jeder Strauch starrte einen ganz
geisterhaft unter seiner Schneekapuze an. Wenn dann der leichte
Schlitten, von flinken Rossen gezogen, unter Schellengeklingel über
die Straße flog — o, ich sage Euch, das war entzückend.“
Dieses Gespräch zeigte, daß Donnel so gut wie Keenan der
Klasse, der sie angehörten und die nach altem Brauch noch den
Namen ‚Poesieklasse‘ trug, alle Ehre machten. Percy war freilich
noch kein ‚Poet‘; allein seine Ideenwelt war nicht minder reich als die
seiner älteren Freunde.
 „Die Schönheit einer solchen Nacht,“ sprach er, „ist mir auch oft
zum Bewußtsein gekommen. Freilich ist es ein Gedanke anderer Art,
welcher der Winternacht für mich einen besonderen, aber lieblichen
Reiz verleiht, nämlich die Erinnerung an die erste Weihnachtsnacht
zu Bethlehem. Die Sterne erinnern mich dann immer an den Stern,
der die heiligen drei Könige führte.“
„Nicht übel, Percy,“ lobte Donnel. „Das ist auch mir ein sehr lieber
Gedanke; nur kann ich ihn nicht gerade so schön aussprechen wie
Du. — Ich glaube übrigens wirklich, daß unter allen Menschen wir
Knaben den meisten Grund haben, uns auf den Winter zu freuen
und den bärbeißigen Alten mit den Eiszapfen im Bart und dem
Nebelatem willkommen zu heißen. Er bringt uns ja Weihnachten mit
all der Liebe und Freude, die wir von Gott und von unsern guten
Eltern nur immer erwarten können.“
„Da fällt mir gerade,“ nahm Keenan das Wort, „die Ode von
Horaz ein, die wir letzte Woche gelesen: ‚Vides, ut alta stet nive
candidum Soracte.‘ Das ist gewiß ein schönes Gedicht; ich habe es
mit großem Vergnügen gelesen. Allein von einer Freude am Winter,
wie w i r sie uns zu besitzen rühmen, ist doch darin keine Rede. Hätte
Horaz etwas von Christus gewußt, welch herrliche Werke hätte er
schaffen können! Gerade das Winterfest Weihnachten ist ja der
schönste Gegenstand für die Dichtkunst.“
„O,“ rief Percy begeistert, „das sieht man so deutlich an Miltons
Hymne auf Christi Geburt, die ich, obgleich ich sie nicht ganz
verstehe, so gern habe.“
„Nimm Dich in acht, Percy,“ sprach Donnel lachend. „Wenn Du
einmal in unsere Klasse kommst, dann gerätst Du so hoch in die
höchste Höhe der Poesie, daß selbst Dein Professor Dir nicht mehr
beikommen kann. Wo hast Du das alles denn gelernt?“
„Von meinen Schwestern, besonders von Julie, der ältesten.
Wenn wir in der Familie zusammen etwas gelesen hatten,
bezeichnete sie mir immer die Stellen, welche am schönsten wären,
und ich lernte sie auswendig.“
 „Ich wünschte mir auch etliche Schwestern von der Art,“ meinte
Keenan, „dann wüßte ich mehr.“
„Ich habe zwei Schwestern,“ versetzte Donnel, „aber wenn sechs
erforderlich waren, um aus Dir, Percy, einen solchen Dichterknaben
zu machen, dann wollte ich, ich hätte deren siebenundzwanzig.“
Percy lachte.
„Sechs sind nicht zu verachten, Johann; aber ich fürchte,
siebenundzwanzig wären doch des Guten zu viel.“
Unter ähnlichen muntern Gesprächen hatten sie bald den Ort
erreicht und schritten auf der Hauptstraße voran.
„Jetzt bitte ich, mich zu entschuldigen,“ sprach dann Percy, der
Erlaubnis hatte, ein Paar Handschuhe und einige andere
Kleinigkeiten zu kaufen. „Ich bin schnell fertig und treffe Euch hier
wieder.“
„Gut, also bis nachher!“
Percy betrat einen Laden — in demselben waren außer
Handschuhen und andern Tuchwaren auch Uhren, Mehl, Eier und
Pflüge feil, was einen Schluß auf die Natur des Städtchens erlaubt
— und erstand, was er wünschte. Allein lange wartete er vergebens
auf seine Gefährten. Er machte sich deshalb schließlich allein auf
den Heimweg, immer um sich schauend, ob sie sich nicht einstellten.
Außerhalb der Stadt, wo die Gebäudereihen der Hauptstraße
sich in vereinzelten Häusern fortsetzten, erblickte er eine Gruppe
Knaben, die alle in der fröhlichsten Stimmung zu sein schienen. Sie
umstanden irgend etwas, das Percy nicht unterscheiden konnte, da
es in ihrer Mitte auf der Erde lag, und das offenbar der Grund ihres
Gelächters und ihrer Freudenrufe war.
Als jedoch Percy näher kam, erkannte er mit Schmerz, daß diese
Freude nichts war als die niedrigste Schadenfreude. Von ihnen
umringt lag auf dem Boden ein feingekleideter junger Mann in
bewußtlosem Zustande, mit einer noch leicht blutenden Wunde am
Kopfe. Der Mann war betrunken. Sein Gesicht zeigte jene
geistlosen, stumpfsinnigen Züge, welche die Folge eines
übermäßigen Genusses von geistigen Getränken sind. Sein Hut lag
schmutzig und zerdrückt neben ihm.
Was aber Percys Mitleid noch viel mehr rege machte, war ein
weiterer Umstand. Neben dem Betrunkenen kniete ein
wohlgekleideter, hübscher Knabe von acht oder neun Jahren, in
vornehmem Anzuge, die Wangen entfärbt vor Furcht und Scheu, die
thränengefüllten Augen mit dem Ausdrucke tiefsten Leides auf den
Bruder gerichtet. Seine Schulbücher waren ihm entfallen und lagen
zerstreut auf dem Boden umher, ein Zeichen, daß er eben auf dem
Wege von der Schule gewesen. Die herzlosen, kleinen Zuschauer
aber waren seine Mitschüler, vermehrt durch ein paar junge
Stadtbummler.
„Lincoln!“ rief das Kind unter Schluchzen, „steh’ doch auf und
geh’ mit nach Hause!“
„Rüttle ihn mal!“ sprach eine rohe Stimme.
„Er hat ganz gut getrunken,“ höhnte ein anderer.
„Warte ein wenig!“ rief ein Dritter von hinten, „ich komme gleich
und zeige Dir, wie man ihn auftreiben kann.“
Percys Herz brannte vor Entrüstung über diese Gefühllosigkeit.
Nicht mehr wie bisher zu neckendem Scherz, sondern in
ernstgemeintem Zorne ballte sich seine Hand.
Der arme Kleine aber schien von diesem Spotte soviel wie nichts
zu merken. Der Bruder allein nahm sein Denken in Anspruch.
„O Lincoln!“ jammerte er mit zitternder Stimme, „komm’, geh’
doch nach Hause! Papa würde ja sehr traurig, wenn er Dich wieder
so daliegen sähe.“
„Sprich doch lauter!“ riet einer. „Vielleicht ist er taub.“
„Das ist ein guter Rat,“ sprach ein anderer. „Aber da hinten sehe
ich Kracher kommen; der weiß sicher noch einen bessern.“
Kracher war ein etwas größerer, nicht gerade friedfertig und
bescheiden aussehender Junge, der, wie es gleich den Anschein
gewann, unter der gesamten Bubenschaft dieses Schlages ein
bedeutendes Ansehen genoß. Man ließ ihn sofort wie einen
Sachverständigen bis zu dem Betrunkenen und dem weinenden
Knaben durch.
„O, der soll bald nüchtern und wach werden!“ versicherte er
selbstbewußt, bückte sich nieder und wollte die Schultern des
Mannes ergreifen.
Allein da sprang das Kind auf, schaute den ungerufenen Helfer
mit flammendem Blicke an, so daß dieser unwillkürlich in seiner
Bewegung innehielt, und rief halb zornig, halb flehend:
„Laß ihn in Ruhe! Rühre ihn nicht an! Er ist mein Bruder!“
Zugleich gab er ihm einen energischen Stoß.
„Das ist mir egal, wessen Bruder er ist,“ erwiderte Kracher, faßte
den Mann bei den Schultern und rüttelte ihn.
Percy aber vermochte jetzt seinen Unwillen nicht länger zu
bemeistern. Er drang bis zu Kracher durch und herrschte ihn mit
erregter Stimme an:
„Schäme Dich, Du gefühlloser Mensch! Wenn Du vor dem Manne
keine Achtung hast, solltest Du doch einem armen, hilflosen Kinde
diesen Schmerz nicht bereiten.“
Kracher, der wie ein Gebieter gewohnt war, jede seiner
Handlungen bewundert und gelobt zu sehen, war bei diesem
gänzlich unerwarteten Widerspruch so überrascht, daß er nicht
gleich eine Entgegnung finden konnte und in den Haufen
zurückwich. Auch seine Gesellen, die es nicht begreifen konnten,
wie ein unbekannter, magerer, fast wie ein Mädchen dreinblickender
Knabe gegen Kracher, den Unbezwinglichen, aufzutreten wagte,
bedurften einiger Besinnung, bis sie sich wieder zu den Scherzen,
wie sie in ihrer Art lagen, erschwangen. So kam es, daß das befreite
Kind für kurze Zeit sich unbelästigt seinem Verteidiger
gegenübersah, den es mit stummer Verwunderung und Dankbarkeit
anblickte.
Allein diese Frist währte nicht lange; dann begann wieder der
Spott, der sich jetzt, wie zu erwarten stand, mit gesteigerter
Heftigkeit gegen Percy wandte.
„Was für eine zarte Puppe!“ hieß es.
„Geh’ doch nach Hause zu Mama, armes Kindchen!“
„O, ich weiß es. Er ist ein Pensionatsjüngelchen.“
„Hast Du auch Erlaubnis auszugehen?“
Dann trat Held Kracher wieder in die Aktion ein und näherte sich
Percy, der ihn unerschrocken, mit einem Blicke voll edler Entrüstung
wie verurteilend ansah.
„Bist Du noch bei Troste, Du Geck?“
Mit diesen verächtlichen Worten wollte sich Kracher an ihm
vorbei wieder dem Manne und dem Kinde zuwenden, um seine
Geringschätzung gegen Percy um so deutlicher kundzugeben.
Allein Percy vertrat ihm den Weg.
„Ihr handelt gemein!“ rief er. „Es könnte einen Stein erweichen,
ein armes Kind in solcher Lage zu sehen. Und Ihr wollt es noch
verhöhnen und quälen!“
„Gemein?“ wiederholte Kracher. „Sag’ uns das nicht noch
einmal!“
„Ja, gemein ist es, gemein!“
„Hört Ihr’s?“ redete jetzt Kracher die Gesellschaft an. „Hört Ihr’s?
Sollen wir uns das gefallen lassen?“
„Er muß Spießruten laufen!“ klang eine Stimme.
„Ja, Spießruten laufen!“ schrie die Bande mit schadenfrohem
Vergnügen.
Kracher ergriff Percy und hielt ihn fest, bis die andern sich in zwei
Reihen, die einander das Gesicht zukehrten, aufgestellt hatten.
Von dem Betrunkenen, welcher der ursprüngliche Grund ihrer
Ansammlung gewesen, war die Aufmerksamkeit jetzt völlig
abgelenkt.
 Der kleine Bruder jedoch beobachtete alles, was vorging, mit
großen Augen. Er wußte sich zwar nicht recht zu erklären, was die
Bubenschar eigentlich vorhabe, erkannte aber so viel, daß es gelte,
seinem Retter Percy ein Leid anzuthun. Er eilte herbei, schlang
beide Arme um Percy und rief, so laut er konnte, um Hilfe. Doch
einige der nächsten Gesellen rissen ihn weg und stießen ihn zurück.
Unterdessen war die Aufstellung vollendet. Kracher brachte also
den wehrlosen Percy an den Anfang dieser Gasse und stieß ihn
hinein. Sofort regnete es Faustschläge und noch viel Schlimmeres
auf ihn, so daß der zarte Knabe, der solche Mißhandlungen kaum
dem Namen nach kannte, schon nach den ersten zwei Schritten
niederfiel. Unsanfte Hände griffen zu, um ihn emporzuziehen. Allein
das widerwärtige Schauspiel fand ein jähes Ende. Denn plötzlich,
Percy wußte nicht warum, stob die ganze Meute auseinander, und
drei der sauberen Brüder stürzten, so lang sie waren, neben Percy
zu Boden.
 24. Kapitel.
Wie zwei Tapfere mit Percy Fersengeld
geben müssen.
onnels und Keenans unerwartete Ankunft und energische
Thätigkeit hatte diese Änderung hervorgebracht. Sie halfen
Percy wieder auf die Füße und sahen sich auf dem
Kampfplatze um.
Die drei gefallenen Buben waren indessen schnell
aufgesprungen und liefen jetzt ebenfalls, was sie laufen konnten.
Doch stand zu befürchten, daß die ganze Schar, mit Kracher an der
Spitze, nicht gesonnen sei, vor Zweien das Feld zu räumen. In der
That hatte Kracher auch nur deshalb die Flucht ergriffen, weil er
glaubte, es sei ein größerer Trupp Zöglinge im Anzuge, ein Irrtum,
der unsern drei Freunden nicht lange zu gute kommen konnte.
„Johann,“ sprach Keenan, „das Gescheiteste ist wegzulaufen. Sie
sind im Nu wieder da, und ihre Wut ist dann um so größer. Was sind
wir zwei gegen ihrer zwanzig? Wer weiß, welche Gemeinheiten wir
dann zu erwarten haben.“
„Was? ausreißen? niemals!“ erklärte Donnel. „Mit einem Dutzend
nehme i c h es auf, und wenn Du mit den übrigen nicht fertig wirst, so
kannst Du mir in Zukunft gestohlen werden. — Hör’, da rufen sie
einander zu. — Kommt nur! Wir können auch liebenswürdig sein,
wenn Ihr es wünscht.“
„Denk’ an Percy, Johann! Für uns beide wäre es ja eine ganz
gesunde Bewegung. Aber Percy ist an diese Sorte Spaß nicht
gewöhnt.“
„Er kann ja allein nach Hause laufen. Dann halten wir die Jungen
auf, damit sie ihn nicht verfolgen. Lauf, Percy! Du hast nichts zu
fürchten.“
Allein Percy — der während des ganzen aufgeregten Vorganges,
wie er ja zu thun gewohnt war, fast beständig gebetet hatte —
machte keine Miene, der Aufforderung zu folgen.
„Nein, ich bleibe bei Euch!“
„Was fällt Dir ein!“ drängte Keenan. „Siehst Du nicht, daß sie
schon Steine aufheben? — Ah, jetzt merke ich’s. Seine Beine haben
wieder etwas abgekriegt. O diese Beine!“
Percy vermochte es in der That nicht, den Schmerz, den er am
Gelenk des rechten Fußes empfand, ganz zu verbergen.
„Wir müssen laufen!“ sprach Donnel ergeben. „Einer muß ihn
wegtragen, und der andere kann doch nicht allein zurückbleiben.“
Während der letzten Worte hatte er Percy ergriffen und
aufgehoben, und jetzt rannten sie davon, so schnell die Füße sie
tragen wollten.
Der Feind hatte diese Wendung der Dinge nicht erwartet,
sammelte sich dann aber um so schneller und lärmender, um den
Entweichenden nachzusetzen. Eine wilde Jagd begann.
Donnel trug seine Bürde mit Leichtigkeit. Allein es war nicht zu
verwundern, daß er trotzdem nicht laufen konnte, als wäre er gar
nicht belastet. Keenan, der sich von Zeit zu Zeit umsah, meldete
ihm, der Haufe ihrer Verfolger komme mit jeder Minute näher.
„Setz’ mich nieder, Donnel!“ bat Percy. „Ich kann ganz gut etwas
laufen. Ich fürchte mich nicht; auch vor einem Steinwurf bin ich nicht
bange. Wenn ich schließlich auch eingeholt würde, so wäre das
lange nicht so schlimm, als wenn Ihr mit in ihre Hände fielet.“
„Ruhig sein, Kleiner!“ sprach Donnel. „Unsere Knochen würden
schon etwas aushalten, aber die Deinen nicht. Meinst Du, um
unsertwillen liefen wir davon?“
„Würdest Du uns denn verlassen,“ fuhr Keenan fort, „wenn wir in
Not wären und Du noch Aussicht hättest uns zu retten? — Holla, sie
sind uns doch verzweifelt nahe. — Ah, da hab’ ich einen Gedanken,
Johann! Du kannst mir Percys Beine geben, dann hast Du nur seine
obere Hälfte zu tragen.“
„Herrlich! Percy, wir halbieren Dich. Sorge nur, daß wir Dich nicht
zerreißen, sonst bringen wir Dich in zwei Stücken nach Hause.“
Mit erneuter Eile setzten sie ihre Flucht fort.
Übrigens war es nicht nur für sie das beste gewesen, daß sie
sich zum Rückzuge entschlossen: auch der Betrunkene, der
mittlerweile aus seinem Zustande erwachte, konnte sich unter
fremder Hilfe mit dem Kinde unbehelligt entfernen.
Donnel und Keenan waren indessen auch jetzt, nachdem sie
Percy halbiert hatten, in ihrem Laufe nicht wenig behindert. Deutlich
merkten sie, wie ihnen die Stimmen der Verfolger stetig näher
kamen, wenn auch langsamer als früher. Bald traf ein Stein Keenan
unterhalb des Kniees.
„Gut gezielt! Das ist gerade die Stelle, wo mein Bein am
zähesten ist. — Hallo, Percy, wir sind bald da. In zwei Minuten
haben wir schon die Brücke erreicht. Nicht bange sein! Du bleibst
am Leben, um auch später noch einmal ausreißen zu können.“
„O, ich habe keine Angst,“ versicherte Percy mit seinem
gewinnenden Lächeln, das Auge voll Vertrauen und Dankbarkeit auf
seine braven Retter heftend. „Ich weiß mich in guter Gesellschaft.“
„Georg,“ rief Donnel plötzlich, „sind das nicht zwei Zöglinge dort
vorne jenseits der Brücke?“
Keenans scharfes Auge bestätigte die Vermutung.
 „Hurra, Ryan und Zieler!“ rief er.
Ryan und Zieler sind den Lesern der früheren Erzählung schon
bekannt. Gehörten sie doch zu jenen neun Helden, deren sich vor
zwei Jahren Tom Playfair so meisterhaft zu erwehren wußte.
Auch Donnel rief ihnen jetzt aus Leibeskräften zu; allein
vergebens, sie waren noch zu weit.
Da ertönte ein lauter, schriller Pfiff. Percy hatte nämlich P.
Middletons Pfeife als Andenken an sein Prärie-Abenteuer
zurückbehalten, so daß sie jetzt abermals ihm und zweien seiner
Freunde zu statten kommen konnte.
Ryan und Zieler wandten sich um. Mit einem Blick hatten sie die
Lage überschaut und stürmten mit beflügelter Eile heran.
Ihr bloßes Erscheinen war genug. Man sah ihnen schon von
ferne an, daß sie wohl im stande waren, Lektionen zu erteilen, die in
keinem Buche der Welt geschrieben standen. Sobald sie deshalb
erkennbar wurden, ergriff die nachjagende Bubenschaft sofort das
Hasenpanier, ohne den geringsten Versuch der Gegenwehr zu
machen.
Besonders Ryan war Ursache ihrer Furcht. Die mächtige,
vierschrötige Gestalt, die erst im Rohbau fertig zu sein schien, und
sein bärbeißiges Gesicht waren allerdings wohl geeignet, auch
einem Beherzten Angst einzuflößen. Ryan hatte, zehn Jahre alt, als
ein lebendiges, nicht gerade lenksames Bürschlein, seinen Einzug in
Maurach gehalten und während der ersten Jahre in beständigem
Krieg mit Professoren und Präfekten gelebt. Nur langsam war es ihm
gelungen, die unbändige Kraft seiner Natur ins rechte Geleise zu
bringen. Am schnellsten hatte er noch die Professoren befriedigt,
wenigstens nachdem er das Stillsitzen in der Klasse in etwa
begriffen; Ryan war nämlich bei weitem nicht so dumm, als er
aussah. Seit mehreren Jahren jedoch stand es mit ihm ganz anders.
Ryan galt mit vollem Recht als tadelloser, vertrauenswürdiger
Zögling und wurde von allen Kameraden wegen seiner Gefälligkeit,
die sich hie und da sogar als Gutherzigkeit äußerte, hochgeschätzt
und geliebt. Sein Äußeres ließ allerdings gerade diese
Eigenschaften am wenigsten vermuten. Im Gegenteil, die Rolle von
Räuberhauptmännern, Christenverfolgern und andern Wüterichen
war bei den theatralischen Darstellungen sein gewöhnlicher Anteil,
und stets lohnte der beste Erfolg die geringe, von ihm aufgewandte
Mühe.
Auf der Brücke angelangt, machten die Flüchtlinge Halt.
„Am Ende sind doch sie noch davongelaufen, nicht wir,“ sprach
Keenan mit Befriedigung.
Percy hatte gleich eine Dichterstelle zur Hand:
„‚Der bess’re Teil der Tapferkeit ist Vorsicht‘, sagte Falstaff, als er
sich tot gestellt hatte.“
Percy stand zwar, an das Geländer der Brücke gelehnt — auf
dieser nämlichen Brücke hatte einst Tom Playfair zu mitternächtiger
Stunde sein Heldenstück geliefert — wieder auf seinen eigenen
Beinen. Doch brauchte es kein scharfes Auge, um zu gewahren, daß
er große Schmerzen empfand.
„Ich habe nun stets gemeint,“ sagte Ryan, als auch er, ein gutes
Stück vor Zieler, auf der Brücke war, „Ihr wäret die friedfertigsten
Menschen von der Welt. Aber jetzt sehe ich Euch im Kriege mit ganz
Jung-Maurach! Was ist denn los gewesen?“
„Percy Wynn hier,“ erklärte Donnel, „hat in seiner Wildheit den
Einfall gehabt, sich auf ihrer zwanzig oder dreißig zu stürzen, um
einmal zu erfahren, was man dabei alles erleben könnte.“
„Ich wollte sie nur bewegen,“ sprach Percy, „einen Knaben,
dessen Bruder ohnmächtig auf der Straße lag, doch nicht zu
verspotten. Es ging mir so zu Herzen, daß ich meinen Unwillen gar
nicht mehr zurückhalten konnte.“
„Jawohl! Wäre Keenan und ich nicht gekommen, um ihn aus der
Patsche zu ziehen, dann hätten sie ihm dafür die Weihnachtstage
gründlich verdorben. Sie wollten ihn gerade Spießruten laufen
lassen.“
„Diese Bengel!“ sprach Ryan voll Abscheu. „Percy, Du bist ein
Ritter sonder Furcht und Tadel. — Aber sieh’ Deine Hand! sie blutet
ja.“
„Ich bin einmal niedergefallen; da muß ich diese Wunde erhalten
haben.“
„Es ist höchste Zeit, daß Du es merkst.“ Mit diesen Worten zog
Ryan sein Taschentuch hervor, um die blutende rechte Hand zu
verbinden.
„Auch Dein Fuß muß verwundet sein. Armer Schelm! Du
vermagst Dich ja kaum aufrecht zu halten. Und Dein Gesicht! Deine
Lippen sind dick aufgeschwollen, als wärest Du ein Negerknabe.
Wirklich! Du siehst noch abscheulicher aus als ich, was viel heißen
will. — Ihr müßt ihn weitertragen und dem Krankenbruder abliefern.
Wenn er nicht gleich mit Pflastern ordentlich geflickt wird, geht er
ganz in Stücke. Donnel, Dein Gesicht hat übrigens auch einen
gehörigen Puff mitbekommen, wahrhaftig!“
„Den gab mir einer in der ersten Hitze, ehe er noch recht wußte,
wen er vor sich hatte. Dann lief er so schnell als möglich davon.“
Donnels Gesicht war in der That stark aufgeschwollen, und die
Geschwulst schien noch immer zuzunehmen.
„Ryan,“ bemerkte jetzt Percy, „ich bin noch immer wegen des
Betrunkenen und des hilflosen Kindes besorgt. Ich fürchte, die
Jungen thun ihnen noch ein Leid an.“
„Das glaube ich kaum,“ beruhigte ihn Donnel. „Es war ja so nahe
bei den Häusern. Was mich wunderte, war nur, daß nicht schon eher
Hilfe kam. Es muß alles sehr schnell hergegangen sein.“
„Doch um Dich zu trösten,“ nahm jetzt Zieler das Wort, der dem
letzten Teile des Gespräches zugehört hatte, „so wollen Ryan und
ich noch schnell hingehen und uns überzeugen, obgleich unsere
Gegenwart kaum mehr nötig sein wird.“
In der Infirmerie gab der Krankenbruder die tröstliche
Versicherung, Percys Verletzungen seien nicht bedenklich und
würden ihn in den Freuden und Festlichkeiten der Weihnachtstage
nicht erheblich stören.
 25. Kapitel.
Zwei Briefe.
m andern Tage erhielt der Rektor des Pensionates folgenden
Brief:
H o c h w ü r d i g e r H e r r P. R e k t o r !
Hochgeehrter Herr!
Unabweisbare Geschäfte machen es mir unmöglich, einer sehr dringenden
Pflicht, die ich seit gestern gegen mehrere Mitglieder Ihrer geschätzten Anstalt
habe, persönlich zu entsprechen.
Ich bin der unglückliche Vater jenes Betrunkenen, der gestern von einem Ihrer
Zöglinge und dessen zwei Freunden in so aufopfernder Weise vor Insulten
geschützt wurde. Nicht ohne ein bitteres Gefühl der Scham schreibe ich diese
Zeilen nieder. Deshalb ist jedoch meine Dankbarkeit gegen jene drei vortrefflichen
Knaben nur um so größer, da sie mir durch ihre edle That wenigstens einen Teil
der Schande erspart haben. Weil ich nun ihre Namen nicht weiß, so ersuche ich
Sie, Hochwürdiger, hochverehrter Herr P. Rektor, an ihrer Stelle meinen
tiefgefühlten Dank entgegennehmen und ihnen übermitteln zu wollen. Der beste
Teil meiner Erkenntlichkeit gebührt ohne Zweifel demjenigen unter ihnen, der von
meinem kleinen Frank, dem Zeugen der Schande seines Bruders, als der kleinste
bezeichnet wird. Er scheint nach Franks Erzählung wirklich der Hauptfaktor
gewesen zu sein. Sobald meine Geschäfte es gestatten, werde ich mir die Ehre
nehmen, selbst in Ihrer Anstalt vorzusprechen und dem kleinen Helden, sowie
dessen Freunden persönlich zu danken.
Zugleich gestehe ich, daß durch den gestrigen Vorfall meine Ansichten über
Ihre Anstalt sich ganz wesentlich geändert haben. Ich bitte um gütige Zusendung
eines Programmes, da mir sehr daran liegt, das Pensionat noch näher kennen zu
lernen.
Mit dem Ausdruck vorzüglichster Hochachtung verbleibe ich
Ew. Hochwürden ergebenster
Arnold Marschall.

Der Name Marschall kam dem Rektor nicht ganz unerwartet.

Dieser reiche Geschäftsmann hatte nämlich zwei Söhne, welche
allenfalls die ihm von Percy beschriebenen Brüder sein konnten.
Herr Marschall war als Feind jeder Religion, vor allem der
katholischen, bekannt.
Sein ältester Sohn hatte zwar nie den besten Leumund besessen
und war für seinen Vater, der trotz allen Religionshasses im Rufe
eines Ehrenmannes stand, eine fortwährende Quelle des Kummers.
Allein ein Laster, das die eigene Verworfenheit in solchem Grade vor
den Augen der Welt bloßstellt wie die Trunksucht, ließ sich in der
vornehmen Familie nicht gut vermuten.
„Der junge Herr Marschall muß sich gegen früher sehr zu seinem
Nachteile verändert haben,“ sprach der Rektor, als er den Brief zu
Ende gelesen. „Früher hat man nie dergleichen von ihm gehört.“
Was Percy anging, so erfuhr er nichts von der Ankündigung des
Besuches, der ihm bevorstand. Der Rektor beabsichtigte, ihm eine
angenehme Überraschung zu bereiten. Es wollte ihn übrigens
bedünken, jener Besuch werde auch für Herrn Marschall selbst wohl
eine größere Bedeutung haben, als im Briefe ausgedrückt war.
Ohne Zögern ging das verlangte Programm an Herrn Marschall
ab. In einem kurzen Begleitschreiben nannte ihm der Rektor die
Namen der drei Zöglinge und bemerkte, Herr Marschall habe mit
vollem Rechte das Benehmen derselben als eine Folge religiöser
Erziehung aufgefaßt; alle drei, vornehmlich der kleinste, Percy
Wynn, hätten eine vortreffliche, aber ausschließlich katholische
Erziehung genossen, wobei jedoch dem Kolleg kein anderes
Verdienst zukomme, als gehütet und gepflegt zu haben, was im
Elternhause gepflanzt worden sei.