Update on Advances in the Pathophysiology and Pathogenesis of IPF

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

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

4. 300 250 Male Female 200 150 100 50 0 45–54 55–64 65–74 75+ Epidemiology of IPF Incidence Prevalence 120 100 Male Female 80 Per Hundred Thousand Per Hundred Thousand 60 40 20 0 45–54 55–64 65–74 75+ Estimated 31,000 New Patients per Year in the United States Estimated 83,000 CurrentPatients 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

6. ATS/ERS Classification of Idiopathic Interstitial Pneumonias ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304. Nicholson AG. Thorax. 2004;59:500-505.

7. Histopathological Patterns of IIPs LUNG INJURY AgeGenetic factorsEnvironmental factorsNature 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.

8. Progression of IPF:Acute Exacerbation vs Slow Decline Traditional View of UIP/IPF Progression Respiratory Function/Symptoms 50% FVC 1 2 3 4 Years FVC = forced vital capacity

9. Progression of IPF:Acute Exacerbation vs Slow Decline Step Theory of UIP/IPF Progression Respiratory Function/Symptoms FVC 50% Acute exacerbation =hits 1 2 3 4 0 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 ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.

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 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.

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 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.

13. Progression of Lung Fibrosis Injury Epithelial cells ? Endothelial cells Capillary 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 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 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.

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) Fibroblast proliferation ECM deposition 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.

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 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.

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

19. Epithelial Restoration Mitogens Stem cell progenitors Fibroproliferation Aberrant Vascular Remodeling Growth factors inhibitors Angiostatic molecules Chemokine antagonists Potential Therapeutic Targets Inflammation Anti-oxidants Cytokines Host Defense Interferon-gamma Prostaglandin-E2 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.