Pathogenesis and Pathophysiology of IPF: Bridging the Gap for the Practitioner

1. Pathogenesis and Pathophysiology of IPF: Bridging the Gap for the Practitioner

2. Learning Objectives • Review and discuss the clinical application of emerging concepts in the pathogenesis of IPF  • Define and identify the hallmark histological pattern found in IPF patients • Explore the evolution of thought regarding the pathogenesis of IPF • Discuss the unpredictable progression of IPF

3. ATS/ERS Classification of Idiopathic Interstitial Pneumonias ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304.

4. Histopathologic Patterns in IIP LUNG INJURY Age Genetic factors Environmental factors Nature of injury Histopathologic Pattern DIP RB - ILD LIP COP NSIP AIP UIP Inflammation Fibrosis Adapted from: Thannickal VJ, et al. Ann Rev Med. 2004;55:395-417. -

5. Current Definition of IPF A distinct type of chronic fibrosing interstitial pneumonia of unknown cause, limited to the lungs, and associated with a surgical lung biopsy showing a histologic pattern of UIP ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664; and 2002;165:277-304.

6. UIP Is the Histologic Hallmark of IPF • Diagnostic criteria of UIP: Clear evidence of temporally heterogeneous areas of normal lung, fibroblastic foci, and microscopic honeycombing • Recent evidence from patient lung biopsies and lung explant studies suggests the coexistence of UIP with other histopathologic patterns, including NSIP and DIP ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664. Flaherty KR, et al. Am J Respir Crit Care Med. 2001;164:1722-1727.

7. US Demographics • Incidence: > 30,000 patients/year • Prevalence: > 80,000 current patients • Age of onset: 40–70 years • Two-thirds > 60 years old at presentation • Males > females ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664. Raghu G, et al. Am J Respir Crit Care Med. 2006;174:810-816.

8. Epidemiology of IPF Incidence Prevalence 120 300 100 250 Male Male Female Female 80 200 Per Hundred Thousand Per Hundred Thousand 60 150 40 100 20 50 0 0 45-54 55-64 65-74 75+ 45-54 55-64 65-74 75+ Estimated 34,000 New Patients Per Year in the United States Estimated 89,000 CurrentPatients in the United States Raghu G, et al. Am J Respir Crit Care Med. 2006;174:810-816.

9. Potential Risk Factors for IPF • Familial • Smoking • Environmental factors (eg, occupational exposure to wood dust or metal dust) • Chronic aspiration associated with gastroesophageal reflux disease (GERD) • Infectious agents ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.

10. Current Hypotheses for the Pathogenesis of IPF • Inflammatory hypothesis: Fibrosis is preceded and driven by a chronic inflammatory cellular infiltrate/reaction • Aberrant wound healing hypothesis: Fibrosis results from abnormal wound healing in response to epithelial injury in the relative absence of inflammation • Multiple hit hypothesis: Fibrosis results from dynamic host inflammatory and repair responses to recurrent or persistent lung injury Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758. Raghu G, Chang J. Clin Chest Med. 2004;25:621-636. Selman M, et al. Drugs. 2004;64:405-430. Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.

11. Inflammatory Hypothesis • Inflammation causes fibrosis • Inflammatory concept was dominant in the 1970s and 1980s • IPF results from unremitting inflammatory response to injury that culminates in progressive fibrosis • Concept supported by collagen vascular disease and chronic extrinsic hypersensitivity pneumonitis, which are inflammatory processes that lead to fibrosis Injury Fibrosis Inflammation Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii. Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.

12. Aberrant Wound Healing Hypothesis • Fibrosis results from an abnormal wound healing response to epithelial injury and activation with a relative absence of inflammation • Supporting evidence: • Inflammation is not a prominent histopathologic finding in UIP • Inflammation is not required for the development of a fibrotic response (animal models) • Clinical measurements of inflammation fail to correlate with stage or outcome in IPF • Anti-inflammatory therapy does not improve disease outcome Selman M, et al. Ann Intern Med. 2001;134:136-151.

13. Multiple Hit Hypothesis Multiple microscopic foci of injury occurring over many years Epithelial damage Wound clot Cellular accumulation • Identify source of injury • ? Genetic predisposition • ? Procoagulant activity • Epithelial apoptosis • Preserve BM integrity • Prevent/interrupt cytokine cascade • Myofibroblast apoptosis Focal (myo)fibroblast proliferation Vascular remodeling Collagen Deposition Antifibrotic agents • Characterize/prevent acute exacerbations • Prevent infections • Thrombotic predisposition • CAD • PHTN Progressive Clinical Course Death Courtesy of Paul W. Noble, MD, and Kevin O. Leslie, MD

14. Support for Multiple Hit Hypothesis • Microarray analysis found 4 categories of genes associated with chronic inflammation/immune responses upregulated in fibrotic lung: • Smooth muscle markers • ECM proteins • Pro-inflammatory cytokines and antioxidants • Immunoglobulins • HRCT study of patients diagnosed with UIP • 55% had mediastinal lymphadenopathy • Possibly suggests ongoing lymphoproliferative process in response to “antigen” Zuo F, et al. Proc Natl Acad Sci USA. 2002;99:6292-6297. Hunninghake GW, et al. Chest. 2003;124:1215-1223.

15. Evolving Unified Hypothesis:Aberrant Response to Persistent Injury Cell death – impaired reepithelialization Epithelial cells Basement Membrane Damage Oxidative Stress Growth factors and other products of epithelial cell injury Procoagulant Activity Myofibroblast TH2-TH1 Balance Cell survival – resistance to apoptosis Vascular Remodeling Collagen – matrix remodeling Courtesy of Paul W. Noble, MD, and Victor J. Thannickal, MD.

16. Vascular Remodeling • 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):S67-69.

17. Vascular Remodeling Is Regulatedby Both Positive and Negative Factors Basic fibroblast growth factor (BFGF) Vascular endothelial growth factor (VEGF) Epidermal growth factor (EGF) Endothelin ELR (+) CXC chemokines Angiostatin Endostatin Thrombospondin-1 Tissue inhibitors of metalloproteases (TIMPs) IFN-inducible ELR (-) CXC chemokines Negative Regulators (Angiostatic) Positive Regulators (Angiogenic) Courtesy of Robert M. Strieter, MD, FCCP.

18. Clinical Progression of IPF • Traditional view: Slow and linear decline in respiratory function ultimately leads to respiratory failure and death • Emerging paradigm: Stepwise progression • Periods of relative stability may be interrupted by acute episodes of worsening lung function that may result in death Noble PW. Am J Respir Cell Mol Biol. 2003;29:S27-S31. King TE, et al. Am J Respir Crit Care Med. 2001;164:1025-1032. Raghu G, et al. N Engl J Med. 2004;350:125-133.

19. Clinical Progression of IPF (cont) • Emerging evidence: • Risk of death is similar across various degrees of disease severity • Question of physiologic measures as predictors of mortality • Acute exacerbations–Nearly half of deaths in a study conducted by Raghu et al occurred prior to physiologic evidence of disease progression. Clinical measures of stability of lung function do not necessarily reflect disease stability • Evidence of improved survival in the absence of any effect on pulmonary function Noble PW. Am J Respir Cell Mol Biol. 2003;29:S27-S31. King TE, et al. Am J Respir Crit Care Med. 2001;164:1025-1032. Raghu G, et al. N Engl J Med. 2004;350:125-133.

20. Progression of IPF:Acute Exacerbation vs Slow Decline Step Theory of UIP/IPF Progression Respiratory Function/Symptoms FVC 50% 1 2 3 4 0 Years = events = Acute exacerbation Adapted from: Noble PW. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S27-S31.

21. Potential Strategies and Targetsof Therapeutic Intervention • Promote repair/regeneration of the alveolar-capillary membrane • Inhibit fibroblast/myofibroblast activation or induce selective apoptosis • Prevent aberrant vascular and extracellular matrix remodeling and basement membrane damage • Limit oxidative stress responses • Augment innate immune responses

22. Take Home Messages • UIP may coexist with other histopathologic patterns in individual patients • The role of inflammation in IPF remains unclear • The pathogenesis of IPF may involve “multiple hits” that perpetuate a cycle of recurrent lung injury and dysregulated host tissue repair • The rate of progression in IPF is unpredictable: rapid declines related to acute exacerbations can occur following periods of relative stability