1. Update on Advances in the Pathophysiology and Pathogenesis of IPF

2. Objective
Discuss the most recent developments in understanding the pathophysiology and pathogenesis of IPF
Objective
This slide section covers the most recent developments in understanding the pathophysiology and pathogenesis of IPF.

3. 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 Definition of Idiopathic Pulmonary Fibrosis
A joint statement of the American Thoracic Society and European Respiratory Society defines IPF as a specific form of chronic fibrosing interstitial pneumonia limited to the lungs and associated with a histologic appearance of usual interstitial pneumonia. The etiology of IPF is unknown.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:
ATS/ERS. Am J Respir Crit Care Med. 2002;165:

4. Epidemiology of IPF Incidence Prevalence
120 50
100
150
200
250
300
45–54
55–64
65–74
75+
Male
Female
100
Male 80
Female
Per Hundred Thousand
Per Hundred Thousand 60 40 20
45–54
55–64
65–74
75+
Epidemiology of IPF
This slide indicates that the incidence and prevalence of IPF increases with age, and that the disease is more common in men than women. With a prevalence of approximately 275 per 100,000 among men over the age of 75, IPF is not a rare disease among older individuals. Because IPF is a chronic disease that is almost uniformly fatal, the ratio of the prevalence to the incidence can provide a crude indication of the duration of survival after diagnosis.
Weycker D, Oster G, Edelsberg J, et al. Prevalence, incidence, and economic costs of idiopathic pulmonary fibrosis. Paper presented at: CHEST, November 2–7, 2002; San Diego, CA.
Estimated 31,000 New Patients per Year in the United States
Estimated 83,000 Current 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.

5. 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
Elucidation of the Natural History and Pathogenesis of IPF
Neither the natural history nor the pathogenesis of IPF is well understood. Elucidation of the complete natural history and pathogenesis of this disease would allow investigation of potentially different mechanisms operative at specific stages of the disease. This knowledge could lead to the development of targeted therapeutic interventions for specific stages of the disease process.

6. ATS/ERS Classification of Idiopathic Interstitial Pneumonias
Histologic Pattern
Clinical/Radiologic/Pathologic Diagnosis
Usual interstitial pneumonia
Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis
Nonspecific interstitial pneumonia
Organizing pneumonia
Cryptogenic organizing pneumonia
Diffuse alveolar damage
Acute interstitial pneumonia
Respiratory bronchiolitis
Respiratory bronchiolitis interstitial lung disease
Desquamative interstitial pneumonia
Lymphoid interstitial pneumonia
ATS/ERS Classification of Idiopathic Interstitial Pneumonias
This table summarizes the recent ATS/ERS classification of the idiopathic interstitial pneumonias, with the requisite histopathologic correlate listed for each. It is important to note that, while a histopathologic pattern of UIP is required for a diagnosis of IPF, other diseases are associated with a UIP pattern. Therefore, the presence of UIP on biopsy does not definitively lead to a clinical diagnosis of IPF.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:
Nicholson, AG, Addis BJ, Bharucha H, et al. Interobserver variation between pathologists in diffuse parenchymal lung disease. Thorax. 2004;59:
ATS/ERS. Am J Respir Crit Care Med. 2002;165:
Nicholson AG. Thorax. 2004;59:

7. Age Genetic factors Environmental factors Nature of injury
Histopathological Patterns of IIPs
LUNG INJURY
Age Genetic factors Environmental factors Nature of injury
– Etiologic agent
– Recurrent vs single
– Endothelial vs epithelial
Histopathologic Pattern
Histopathological Patterns of IIPs
A recent review of the mechanisms of pulmonary fibrosis by Thannickal and colleagues explained how histopathologic changes in the lung can be quite diverse, with overlapping patterns of inflammation and fibrosis.
“Histopathologic patterns of idiopathic interstitial pneumonias (IIPs) represent a spectrum of tissue reactions with varying degrees of inflammation and fibrosis. This reaction pattern probably depends on multiple factors, including age, genetic susceptibility, environmental factors, and perhaps the nature of the injurious agent.”
Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:
DIP
RB-ILD
LIP
COP
NSIP
AIP
UIP
Inflammation
Fibrosis
Thannickal VJ, et al. Annu Rev Med. 2004;55:

8. Progression of IPF: Acute Exacerbation vs Slow Decline
Traditional View of UIP/IPF Progression
Function/Symptoms
Respiratory
FVC
50%
Progression of IPF: Acute Exacerbation vs Slow Decline
The traditional view of IPF progression involved a slow and steady decline in respiratory function as illustrated by this chart. According to this view, a slow progressive decline in lung function ultimately leads to respiratory failure. 1 2 3 4
Years
FVC = forced vital capacity

9. Progression of IPF: Acute Exacerbation vs Slow Decline
Step Theory of UIP/IPF Progression
Function/Symptoms
Respiratory
FVC
50%
Acute exacerbation
Progression of IPF: Acute Exacerbation vs Slow Decline
Emerging evidence suggests that IPF may involve multiple injuries or “hits” to the lung over a period of time, and these hits lead to acute exacerbations that result in periods of more rapid decline in lung function. In other words, this step theory of IPF progression posits that IPF involves many subclinical events with superimposed acute exacerbations that lead to functional decline. These acute exacerbations can be mild or severe and lead to a precipitous decline in respiratory function, and in some cases, respiratory failure and death.
Idiopathic Pulmonary Fibrosis. Proceedings of the 1st Annual Pittsburgh International Lung Conference. October Am J Respir Cell Mol Biol. 2003;29(3 suppl):S1-S105. 1 2 3 4
=hits
Years
Am J Respir Cell Mol Biol. 2003;29(3 suppl):S1-S105.

10. 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
UIP is the Histologic Hallmark of IPF
The ATS/ERS identifies UIP as the histological abnormality essential to the diagnosis of IPF. The diagnostic criteria for UIP include a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, fibrosis, and end-stage honeycomb change. Areas of normal pulmonary parenchyma must be interspersed throughout a background of extensive fibrosis and honeycombing.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med. 2000;161:
ATS/ERS. Am J Respir Crit Care Med. 2000;161:

11. 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
Multiple Hypotheses for the Pathogenesis of IPF
The exact mechanisms underlying the development of IPF remain unknown. While no theory of disease pathogenesis has been proven, several hypotheses have been proposed and are currently being studied. This slide provides a summary of 3 prevailing hypotheses for the pathogenesis of IPF.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis:current trends in management Clin Chest Med. 2004;25: , v.
Strieter RM, Belperio JA, Keane MP. CXC chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Clin Chest Med. 2004;25: , v.
Strieter R. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.

12. 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
Inflammatory Hypothesis
In the 1970s and 1980s, the dominant hypothesis regarding IPF pathogenesis held that IPF resulted from an unremitting inflammatory response to injury culminating in progressive fibrosis. At that time, many patients with diseases that we now recognize as distinct clinical entities other than IPF were lumped under the diagnosis of IPF. As we have learned more about IPF and improved our ability to diagnose IPF, the role of inflammation and the efficacy of corticosteroids in the treatment of IPF have become increasingly questionable.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25: , v.
Inflammation
Fibrosis
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Clin Chest Med. 2004;25: , v.

13. Progression of Lung Fibrosis
Injury
Epithelial cells ?
Endothelial
cells
Capillary
Progression of Lung Fibrosis
While the etiology of IPF remains unknown, several recent observations have led to a theory that IPF is the result of an aberrant wound healing process.
According to this theory, injury to the alveolar epithelial and capillary wall lining stimulates the release of molecules that damage the basement membrane. In the absence of an appropriate substrate, re-epithelialization and re-endothelialization cannot occur. In an attempt to “wall off” the exposed area, chemokines and growth factors recruit fibroblasts and endothelial cells. Recruited fibroblasts/myofibroblasts are then stimulated to produce collagen and other matrix components.
Slide courtesy of Paul Noble, MD.
Slide courtesy of Paul Noble, MD.

14. Tissue Model of Lung Fibrosis
Cell death
Epithelial cells
Endothelial
cells
Growth factors and other
products of epithelial
cell Injury
Capillary
Myofibroblast
Tissue Model of Lung Fibrosis
Specifically, injury to the alveolar-capillary walls leads to tissue damage and cell death. This cell death is accompanied by damage to the basement membrane and the release of a variety of factors, including growth factors and cytokines. Many of these factors stimulate fibroblasts/myofibroblasts to produce extracellular matrix components (particularly collagen), and can lead to dysregulated repair of the epithelial/endothelial barrier. In the end, the formation of fibrotic regions of extracellular matrix proteins and myofibroblasts impedes the recovery of the normal alveolar wall.
Slide courtesy of Paul Noble, MD.
Collagen
Slide courtesy of Paul Noble, MD.

15. 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
Noninflammatory (multiple hit) Hypothesis
The model of aberrant wound healing described on the previous 2 slides forms the basis for the second prevailing hypothesis of the pathogenesis of IPF. This hypothesis postulates that pulmonary fibrosis results from epithelial injury and abnormal wound repair in the absence of inflammation. Initial injury to the distal pulmonary parenchyma causes repeated injury to the epithelium and endothelium, and epithelial and endothelial apoptosis. The loss of the alveolar epithelium and endothelium exposes the basement membrane to oxidative injury and degradation. Failure of re-epithelialization and re-endothelialization provides the stimulus for persistent production of profibrotic growth factors, persistent fibroblast proliferation, excessive ECM deposition, and progressive fibrosis.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25: , v.
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JI 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004;64:
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Clin Chest Med. 2004;25: , v.
Selman M, et al. Drugs. 2004;64:

16. Noninflammatory (multiple hit) Hypothesis
Recurrent pulmonary injury
Epithelial/
endothelial injury and apoptosis
TGF-b = 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 growth factors (TGF-b, PDGF, IGF-1)
Noninflammatory (multiple hit) Hypothesis
This is a simple schematic representation of the non-inflammatory (multiple hit) hypothesis discussed on the previous slide.
Recurrent pulmonary injury leads to epithelial cell injury and apoptosis, resulting in loss of the basement membrane integrity, and ultimately leading to failure of re-epithelialization and re-endothelialization. This process stimulates the release of profibrotic growth factors including TGF-, PDGF, and IGF-1, as well as proliferation of fibroblasts and excessive deposition of extracellular matrix components. These events ultimately lead to progressive fibrosis with the loss of lung architecture.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25: , v.
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004;64:
Fibroblast proliferation
ECM deposition
Progressive fibrosis with loss of lung architecture
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Clin Chest Med. 2004;25: , v.
Selman M, et al. Drugs. 2004;64:

17. 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
Chemokine imbalance
Increased angiogenesis
Vascular Remodeling Hypothesis
The presence of aberrant vascular remodeling in IPF was originally identified in the 1960s. Early studies demonstrated neovascularization in areas of fibrosis and anastomoses between the systemic and pulmonary microvasculature. These findings underlie the vascular remodeling hypothesis of IPF pathogenesis. The hypothesis postulates that vascular remodeling in areas of fibrosis may support fibroplasia and that development of anastomoses between the systemic and pulmonary microvasculature may contribute to increased right-to-left shunt and hypoxemia in IPF patients upon exertion or in conjunction with secondary pulmonary hypertension.
A fundamental component of this hypothesis is the idea that angiogenesis, which leads to aberrant vascular remodeling, is the result of an imbalance between pro-angiogenic chemokines (IL-8, ENA-78) and angiostatic, IFN-inducible chemokines (IP-10, MIG, ITAC) that favor augmented angiogenic activity.
In animal models, expression of an angiogenic chemokine and the angiostatic chemokine, IP-10 and ITAC, directly and inversely, respectively, correlate with the extent of fibrosis during bleomycin-induced pulmonary fibrosis.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Strieter RM, Belperio JA, Keane MP. CXC Chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.
Aberrant
vascular
remodeling
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Strieter RM, et al. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.

18. Defects in Host Defense Mechanisms May Contribute to Fibrosis
Defects in endogenous host defense mechanisms (eg, IFN-g, PGE2 production) that limit fibrosis after acute lung injury may contribute to progressive fibrosis
Defects in Host Defense Mechanisms May Contribute to Fibrosis
The temporal heterogeneity of fibrotic lesions in IPF suggests that host factors that limit the extent of fibrosis after lung injury may be an important component of disease pathogenesis. It is suggested that a failure of sufficient antifibrotic responses to injury, such as deficiencies in IFN- or prostaglandin E2, may contribute to disease progression. Therefore, augmentation of host defense mechanisms may be a novel approach to therapy for IPF.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.

19. Potential Therapeutic Targets
Inflammation
Epithelial Restoration
Mitogens
Stem cell progenitors
Aberrant Vascular Remodeling
Angiostatic
molecules
Anti-oxidants
Cytokines
Fibroproliferation
Growth factors inhibitors
Chemokine
antagonists
Host Defense
Interferon-gamma
Prostaglandin-E2
Potential Therapeutic Targets
This is a schematic representation of a number of potential therapeutic targets that can be proposed based on the various hypotheses for the pathogenesis of IPF. The potential therapeutic targets may include the following: diminution of inflammation through the use of anti-oxidants and cytokines; restoration of the alveolar epithelium through the use of epithelial mitogens or stem cell progenitors; the reduction of aberrant vascular remodeling affected by angiostatic molecules; inhibition of fibroproliferation mediated by growth factor inhibitors and chemokine antagonists; and regulation of host defense mediators such as interferon-gamma, and prostaglandins.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25: , v.
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004;64:
Burdick MD, Murray LA, Keane MP, et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med. 2005;171:
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Clin Chest Med. 2004;25: , v.
Selman M, et al. Drugs. 2004; 64:
Burdick MD, et al. Am J Respir Crit Care Med. 2005;171: