Update on Advances in the

Pathophysiology and
Pathogenesis of IPF
 Objective

• Discuss the most recent developments in

understanding the pathophysiology and
pathogenesis of IPF
 ATS/ERS Definition of Idiopathic
Pulmonary Fibrosis

• A type of chronic fibrosing interstitial pneumonia

• Unknown etiology limited to the lungs

• Associated with a histologic pattern of usual

interstitial pneumonia (UIP)

ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304.

 Epidemiology of IPF
Incidence Prevalence
120 300
Per Hundred Thousand

Per Hundred Thousand

100 250
Male Male
80 Female 200 Female

60 150

40 100

20 50

0 0
45–54 55–64 65–74 75+ 45–54 55–64 65–74 75+

Estimated 31,000 New Patients Estimated 83,000 Current

per Year in the United States Patients in the United States

Weycker D, et al. Prevalence, Incidence, and Economic Costs of Idiopathic Pulmonary

Fibrosis. Paper presented at: CHEST 2002, November 2-7, 2002; San Diego, CA.
 Elucidation of the Natural History
and Pathogenesis of IPF
• Allows investigation of potentially different
mechanisms operative at early, intermediate,
and end-stages

• Facilitates implementation of targeted

therapeutic intervention at specific stages of
disease
 ATS/ERS Classification of
Idiopathic Interstitial Pneumonias
Histologic Pattern Clinical/Radiologic/Pathologic Diagnosis
Idiopathic pulmonary fibrosis/cryptogenic fibrosing
Usual interstitial pneumonia
alveolitis
Nonspecific interstitial
Nonspecific interstitial pneumonia
pneumonia
Organizing pneumonia Cryptogenic organizing pneumonia
Diffuse alveolar damage Acute interstitial pneumonia
Respiratory bronchiolitis Respiratory bronchiolitis interstitial lung disease
Desquamative interstitial
Desquamative interstitial pneumonia
pneumonia
Lymphoid interstitial pneumonia Lymphoid interstitial pneumonia

ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304.

Nicholson AG. Thorax. 2004;59:500-505.
Histopathological Patterns of IIPs
LUNG INJURY

Age
Genetic factors
Environmental factors
Nature of injury
– Etiologic agent
– Recurrent vs single
– Endothelial vs epithelial

Histopathologic Pattern

DIP RB-ILD LIP COP NSIP AIP UIP

Inflammation
Fibrosis

Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.

 Progression of IPF:
Acute Exacerbation vs Slow Decline
Traditional View of UIP/IPF Progression
Function/Symptoms
Respiratory

FVC
50%

1 2 3 4
FVC = forced vital capacity Years
 Progression of IPF:
Acute Exacerbation vs Slow Decline
Function/Symptoms
Step Theory of UIP/IPF Progression
Respiratory

FVC
50%

Acute exacerbation

0 1 2 3 4 =hits
Years

Am J Respir Cell Mol Biol. 2003;29(3 suppl):S1-S105.

UIP is the Histologic Hallmark of IPF

• Diagnostic criteria of UIP: clear

evidence of temporally heterogeneous
areas of normal lung, active fibrosis,
and end-stage honeycomb fibrosis
• All areas of the lung are not involved

ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.

 Multiple Hypotheses for the
Pathogenesis of IPF
• Inflammation causes fibrosis
• Noninflammatory (multiple hit) hypothesis:
fibrosis results from epithelial injury and
abnormal wound healing in the absence of
chronic inflammation
• Vascular remodeling: aberrant vascular
remodeling supports fibrosis, and may contribute
to increased shunt and hypoxemia

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25: 621-636, v.
Strieter R. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.
 Inflammatory Hypothesis
• Inflammation causes fibrosis
– Inflammatory concept was dominant in the 1970s and
1980s
 IPF resulted from unremitting inflammatory response
to injury culminating in progressive fibrosis
– Role of inflammation remains controversial
 Lack of efficacy of corticosteroids

Injury Inflammation Fibrosis

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.
 Progression of Lung Fibrosis

Injury

Epithelial cells

?
Endothelial
cells
Capillary

Slide courtesy of Paul Noble, MD.

 Tissue Model of Lung Fibrosis
Cell death
Epithelial cells
Endothelial
cells

Growth factors and other

products of epithelial Capillary
cell Injury

Myofibroblast

Collagen

Slide courtesy of Paul Noble, MD.

 Noninflammatory (multiple hit)
Hypothesis
• Fibrosis results from epithelial/endothelial injury
and abnormal wound healing in the absence of
chronic inflammation
– Recurrent, unknown injury to distal pulmonary parenchyma
causes repeated epithelial cell injury and apoptosis
– Loss of alveolar epithelium exposes basement membrane
to oxidative injury and degradation
– Failure of re-epithelialization/re-endothelialization provides
stimulus for persistent profibrotic growth factor production,
persistent fibroblast proliferation, excessive deposition of
ECM, and progressive fibrosis

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.
Selman M, et al. Drugs. 2004;64:405-430.
 Noninflammatory (multiple hit) Hypothesis
Epithelial/
Recurrent
endothelial
pulmonar
injury and
y injury
apoptosis TGF-= transforming growth factor-beta
PDGF = platelet derived growth factor
IGF-1 = insulin-like growth factor-1
Loss of basement
membrane

Failure of
re-epithelialization/
re-endothelialization
Release of
profibrotic
Fibroblast ECM growth factors
proliferatio depositio (TGF-, PDGF,
n n IGF-1)

Progressive fibrosis with loss of

lung architecture

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v. Selman M, et al. Drugs. 2004;64:405-430.
 Vascular Remodeling Hypothesis
• Aberrant vascular remodeling supports fibrosis and may
contribute to increased shunt and hypoxemia
 Increased angiogenesis results from imbalance of pro-angiogenic
chemokines (IL-8, ENA-78) and anti-angiogenic, IFN-inducible
chemokines (IP-10)
 Vascular remodeling leads to anastomoses between the
systemic/pulmonary microvasculature, increasing right-to-left shunt,
contributing to hypoxemia

Fibrosis
Chemokin
e Increased
imbalance angiogenesis
Aberrant
vascular
remodeling

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Strieter RM, et al. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.
Defects in Host Defense Mechanisms
May Contribute to Fibrosis
• Defects in endogenous host defense
mechanisms (eg, IFN-, PGE2 production) that
limit fibrosis after acute lung injury may
contribute to progressive fibrosis

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

 Potential Therapeutic Targets
Epithelial Aberrant
Inflammation Restoration Vascular
Remodeling
Anti-oxidants Mitogens
Angiostatic
Cytokines Stem cell molecules
progenitors

Fibroproliferatio Host Defense

n
Growth factors Interferon-gamma
inhibitors
Prostaglandin-E2

Chemokine
antagonists

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.
Selman M, et al. Drugs. 2004; 64:405-430.
Burdick MD, et al. Am J Respir Crit Care Med. 2005;171:261-268.