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. Epidemiology of IPF Estimated 83,000 Current Patients in the United States Estimated 31,000 New Patients per Year in the United States 0 50 100 150 200 250 300 45–5455–6465–7475+ Male Female 0 20 40 60 80 100 120 45–5455–6465–7475+ Male Female 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. Prevalence Incidence Per Hundred Thousand

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 Histologic PatternClinical/Radiologic/Pathologic Diagnosis Usual interstitial pneumonia Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis Nonspecific interstitial pneumonia Organizing pneumoniaCryptogenic organizing pneumonia Diffuse alveolar damageAcute interstitial pneumonia Respiratory bronchiolitisRespiratory bronchiolitis interstitial lung disease Desquamative interstitial pneumonia Lymphoid interstitial pneumonia ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304. Nicholson AG. Thorax. 2004;59:500-505.

7. Histopathological Patterns of IIPs Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417. Age Genetic factors Environmental factors Nature of injury – Etiologic agent – Recurrent vs single – Endothelial vs epithelial Histopathologic Pattern DIPRB-ILDLIPCOPNSIPAIPUIP Inflammation Fibrosis LUNG INJURY

8. 50% Years Respiratory Function/Symptoms 1234 FVC Traditional View of UIP/IPF Progression Progression of IPF: Acute Exacerbation vs Slow Decline FVC = forced vital capacity

9. 50% Years Respiratory Function/Symptoms 123 Acute exacerbation Step Theory of UIP/IPF Progression Progression of IPF: Acute Exacerbation vs Slow Decline FVC 0 4 Am J Respir Cell Mol Biol. 2003;29(3 suppl):S1-S105. =hits

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. 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 Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii. Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v. InjuryInflammationFibrosis Inflammatory Hypothesis

13. Injury Epithelial cells Slide courtesy of Paul Noble, MD. Progression of Lung Fibrosis Capillary Endothelial cells ?

14. Epithelial cells Collagen Myofibroblast Cell death Growth factors and other products of epithelial cell Injury Slide courtesy of Paul Noble, MD. Tissue Model of Lung Fibrosis Capillary Endothelial cells

15. 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

16. Recurrent pulmonar y injury Epithelial/ endothelial injury and apoptosis Loss of basement membrane Failure of re-epithelialization/ re-endothelialization ECM depositio n Fibroblast proliferatio n Release of profibrotic growth factors (TGF- , PDGF, IGF-1) Progressive fibrosis with loss of lung architecture TGF -  = transforming growth factor-beta PDGF = platelet derived growth factor IGF-1 = insulin-like growth factor-1 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. 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 Chemokin e imbalance Increased angiogenesi s Fibrosis 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. Vascular Remodeling Hypothesis Aberrant vascular remodeling

18. 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.

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