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Pathobiology of IPF

Pathobiology of IPF. Glenn D. Rosen, MD Associate Professor of Medicine Stanford University School of Medicine Stanford, California. Faculty Disclosure.

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Pathobiology of IPF

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  1. Pathobiology of IPF Glenn D. Rosen, MD Associate Professor of Medicine Stanford University School of Medicine Stanford, California

  2. Faculty Disclosure It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a faculty member with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all faculty conflicts of interest prior to the release of this activity. Glenn D. Rosen, MD, has received grants/research support from the Pulmonary Fibrosis Foundation, and has served as a consultant for Boehringer Ingelheim, Gilead Corporation, and Takeda Pharmaceuticals.

  3. Learning Objective • Explain the pathophysiology of IPF and the therapeutic approaches to different steps in the disease process

  4. Where Is the Problem?

  5. Phenotypes in IPF Molecular Radiographic Pathologic Clinical

  6. Potential Risk Factors Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824. • Cigarette smoking – especially if > 20 pack years • Environmental exposures • Increased inorganic particles in lymph nodes on autopsy in IPF patients • Metal and wood dusts: brass, lead, steel, pine • Farming: animal and vegetable dust • Raising birds, hair dressing, stone cutting • Microbial agents • Herpes viruses – EBV, HHV-7, HHV-8, CMV, as well as Hep C • Isolated in IPF lungs, c/b concomitant immunosuppression • No definite conclusion for role of infection

  7. Familial Idiopathic Interstitial Pneumonia • Two or more family members have the same disease • Autosomal dominant pattern of inheritance with reduced penetrance • Accounts for ~10–20% of IPF cases • Earlier age of onset than sporadic form • Can display pathologic heterogeneity, eg, NSIP, COP, sarcoidosis • Strongest risk factor for IPF (OR = 6) Garcia-Sancho C, et al. Respir Med. 2011;105(12):1902-1907.

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

  9. Critical Role for Transforming Growth Factor- in Fibrosis • Delivering active TGF-β by gene therapy causes tissue fibrosis • Anti-TGF-β therapies (antibodies, IFN-g, pirfenidone, decorin) inhibit fibrosis in animal models and are in clinical trials • TGF-β directly stimulates matrix production by fibroblasts and inhibits matrix degradation • TGF-β induces epithelial mesenchymal transition (EMT) • TGF-β is produced predominantly by alveolar epithelial cells and macrophages in IPF lung Coward WR, et al. Ther Adv Respir Dis. 2010;4(6):367-388.

  10. What Is the Origin of Myofibroblasts in IPF? Imatinib Imatinib Scotton CJ, et al. Chest. 2007;132(4):1311-1321.

  11. What Is the Origin of Fibroblasts/Myofibroblasts During IPF Pathogenesis? • Classical theory: • Tissue injury → activation and proliferation of resident fibroblasts → deposition of ECM constituents • Contemporary theories: • Injury induces epithelial cells → mesenchymal phenotype (fibroblast/myofibroblast) → fibroproliferation • Circulating fibrocytes → behave like mesenchymal stem cells → extravasate into injury site → ECM deposition → fibrosis Scotton CJ, et al. Chest. 2007;132(4):1311-1321.

  12. Pericytes • Interstitial cells surrounding blood vessels which express markers NG2 and PDGFRb • Origin of fibroblasts that secrete ECM in renal fibrosis and scar tissue after spinal cord injury • Accumulate in response to bleomycin in mouse lung and in IPF lung Rock JR, et al. Proc Natl Acad Sci USA. 2011;108(52):E1475-1483.

  13. Biomarkers for IPF • Matrix Metallo-Proteases (MMP1/MMP3/MMP7)1 • Surfactant proteins A & D2,KL-63 • CCL2/CCL18, TGFβ-14 • Collagen turnover products (PIIINP, ICTP, PYD/DYD)5 • Emerging markers (MMP7, ICAM-1, IL-8, VCAM-1, and S100A12) in serum predicted poor overall survival, poor transplant-free survival, and poor progression-free survival • Rosas IO, et al. PLoS Med. 2008;5:e93; Yamashita CM, Am J Path. 2011;179:1733-1745. • Nakamura M, et al. Nihon Kokyuki Gakkai Zasshi. 2007;45:455-459. • Greene KE, et al. Eur Respir J. 2002;19:439-446. • Yokoyama A, et al. Am J Respir Crit Care Med. 1998;158:1680-1684. • Richards, TJ, et al. Am J Respir Crit Care Med. 2012;185(1):67-76. • Schaberg T, et al. Eur Respir J. 1994;7:1221-1226. Hiwatari N, et al. Tohoku J Exp Med. 1997;181(2):285-95. Froese AR, et al. ATS 2008 poster 907.

  14. Biomarker Applications in IPF Zhang Y, Kaminski N. Curr Opin Pulm Med. 2012;18(5):441-446.

  15. Genetic Changes in Sporadic IPF SNP: single nucleotide polymorphism Steele MP, Schwartz DA . Annu Rev Med. 2013;64:12.1-12.12.

  16. Telomerase-Normal Functionthe Key to Long Life? • Telomeres act as caps to keep the sticky ends of chromosomes from randomly clumping together • Telomerase adds telomeres to the end of chromosomal DNA and allows for rejuvenation/regeneration • As DNA replicates, loss of telomeres causes shortening of DNA, which can lead to dysfunctional cells and cell death Greider CW, Blackburn EH. Scientific American.1996;274:92-96.

  17. What Goes Wrong? Armanios MY, et al. N Engl J Med. 2007;356(13):1317-1326. Cronkhite JT, et al. Am J Respir Crit Care Med. 2008;178:729-737. • Mutations decreasing telomerase activity lead to poor regeneration of DNA and cell death • Telomerase implicated in many diseases and a genetic disease (dyskeratosis congenita) with telomerase mutation develops lung fibrosis

  18. Frequency of Mutations in IPF Garcia CK. Proc Am Thorac Soc. 2011;8(2):158-162.

  19. Telomeres and Fibrosis Thannickal VJ, Lloyd JE. Am J Respir Crit Care Med. 2008;178:663-665.

  20. GERD and IPF • Approximately 50–70% of IPF patients have GERD • 50% have GERD symptoms • Increased incidence of hiatal hernia in IPF patients • Increased incidence of GER in IPF due to microaspiration as an important trigger or due to GER simply reflecting larger negative swings in intrathoracic pressure in IPF as result of reduced pulmonary compliance correlating with more severe pulmonary fibrosis? • Role of GERD in asymmetric IPF (AIPF) => very strong concordance with choice of sleeping position (dependent lung more extensively involved) • Treatment of GERD associated with less fibrosis and improved survival in IPF patients Tcherakian C, et al. Thorax. 2011;66(3):226-231. Raghu G, et al. Eur Respir J. 2006;27(1):136-142. Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):1390-1394.

  21. Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):1390-1394.

  22. New Paradigm forInterstitial Pulmonary Fibrosis Epithelial Injury Inflammation Fibroblast proliferation and differentiation Granulation tissue formation Polarization of immune response Failure of re-epithelialization TGF-β activation Th1 cytokines Th2 cytokines TGF-β activation Fibrosis Apoptosis Angiogenesis ECM deposition

  23. Selected Recent Controlled Trials in IPF Adapted from Kevin Brown, MD

  24. Current Drug Trials in IPF http://www.clinicaltrials.gov. Accessed October 2012.

  25. Adult Lung TransplantationKaplan-Meier Survival By Diagnosis(Transplants: January 1990–June 2007) 100 Alpha-1 (N = 2,085) CF (N = 3,746) COPD (N = 8,812) IPF (N = 4,695) IPAH (N = 1,065) Sarcoidosis (N = 597) 75 HALF-LIFE Alpha-1: 6.1 Years; CF: 7.0 Years; COPD: 5.1 Years; IPF: 4.3 Years; IPAH: 5.6 Years; Sarcoidosis: 5.3 Years Survival comparisons Alpha-1 vs CF: P < 0.0001 Alpha-1 vs COPD: P < 0.0001 Alpha-1 vs IPF: P < 0.0001 Alpha-1 vs Sarcoidosis: P = 0.0380 CF vs COPD: P < 0.0001 CF vs IPF: P < 0.0001 CF vs IPAH: P < 0.0001 CF vs Sarcoidosis: P < 0.0001 IPAH vs IPF: P = 0.0046 COPD vs IPF: P < 0.0001 50 Survival (%) 25 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years Christie JD, et al. J Heart Lung Transplant. 2009;28:1031-1049.

  26. Lung Stem Cells: Ready or Not? Wetsel RA, et al. Annu Rev Med. 2011;62:95-105.

  27. Generation of Lung Alveolar Cells From Embryonic Stem Cells Wetsel RA, et al. Annu Rev Med. 2011;62:95-105.

  28. Clinical Management of Patients With IPF Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

  29. Proposed Pathogenesis of IPF Steele MP, Schwartz DA . Annu Rev Med. 2013;64:12.1-12.12

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