Pathobiology of IPF

Glenn D. Rosen, MDAssociate Professor of Medicine

Stanford University School of MedicineStanford, California

Faculty DisclosureIt 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.

Learning Objective

• Explain the pathophysiology of IPF and the therapeutic approaches to different steps in the disease process

Where Is the Problem?

Phenotypes in IPF

Radiographic Pathologic

Molecular

Clinical

Potential Risk Factors

• 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

Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

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.

IPF Pathogenesis

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

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.

Scotton CJ, et al. Chest. 2007;132(4):1311-1321.

What Is the Origin of Myofibroblasts in IPF?

Imatinib

Imatinib

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.

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.

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

1. Rosas IO, et al. PLoS Med. 2008;5:e93; Yamashita CM, Am J Path. 2011;179:1733-1745.2. Nakamura M, et al. Nihon Kokyuki Gakkai Zasshi. 2007;45:455-459.

Greene KE, et al. Eur Respir J. 2002;19:439-446.3. Yokoyama A, et al. Am J Respir Crit Care Med. 1998;158:1680-1684.4. Richards, TJ, et al. Am J Respir Crit Care Med. 2012;185(1):67-76. 5. 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.

Biomarker Applications in IPF

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

Steele MP, Schwartz DA . Annu Rev Med. 2013;64:12.1-12.12.

Genetic Changes in Sporadic IPF

SNP: single nucleotide polymorphism

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.

What Goes Wrong?• 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

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.

Frequency of Mutations in IPF

Garcia CK. Proc Am Thorac Soc. 2011;8(2):158-162.

Telomeres and Fibrosis

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

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.

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

New Paradigm forInterstitial Pulmonary Fibrosis

Epithelial Injury

Inflammation

Polarization of immune response

Fibroblast proliferation and

differentiation

TGF-β activationApoptosisAngiogenesis

TGF-β activation

ECM deposition

Th1 cytokines

Th2 cytokines

Granulationtissue

formationFailure of

re-epithelialization

Fibrosis

Selected Recent Controlled Trials in IPF

Year Study Agent Result Reference2005 IFIGENIA N-

acetylcysteinePos Demedts M, et al. NEJM 2005

2009 GIPF-007 IFN- Neg King TE Jr, et al. Lancet 20092010 Shionogi Pirfenidone Neg Taniguchi H, et al. ERJ 20102010 STEP Sildenafil Neg Zisman D, et al. NEJM 20102011 BUILD-3 Bosentan Neg King TE Jr, et al. AJRCCM 20112011 CAPACITY Pirfenidone Pos/Neg Noble PW, et al. Lancet 20112011 BIBF-1120 BIBF-1120 Neg Richeldi L, et al. NEJM 20112012 PANTHER Pred/Aza/NAC Neg Raghu G, et al. NEJM 20122012 ACE Warfarin Neg Noth I, et al. AJRCCM 20122012 IPF CNTO888 Neg ClinicalTrials.gov NCT00786201

Adapted from Kevin Brown, MD

Current Drug Trials in IPF

Agent Target N Phase QAX576 IL-13 40 2STX-100 Integrin avb6 32 2Pirfenidone (ASCEND) Oxidation 500 3FG-3019 CTGF 84 2Sirolimus mTOR 45 N/AAM152 LPA1 Receptor 300 2GS-6624 (AB0024) LOXL2 48 1

http://www.clinicaltrials.gov. Accessed October 2012.

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

Adult Lung TransplantationKaplan-Meier Survival By Diagnosis (Transplants: January 1990–June 2007)

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10 11 12Years

Surv

ival

(%)

Christie JD, et al. J Heart Lung Transplant. 2009;28:1031-1049.

Alpha-1 (N = 2,085) CF (N = 3,746) COPD (N = 8,812)IPF (N = 4,695) IPAH (N = 1,065) Sarcoidosis (N = 597)

Survival comparisonsAlpha-1 vs CF: P < 0.0001Alpha-1 vs COPD: P < 0.0001 Alpha-1 vs IPF: P < 0.0001Alpha-1 vs Sarcoidosis: P = 0.0380CF vs COPD: P < 0.0001CF vs IPF: P < 0.0001CF vs IPAH: P < 0.0001CF vs Sarcoidosis: P < 0.0001IPAH vs IPF: P = 0.0046COPD vs IPF: P < 0.0001

Lung Stem Cells: Ready or Not?

Wetsel RA, et al. Annu Rev Med. 2011;62:95-105.

Generation of Lung Alveolar Cells From Embryonic Stem Cells

Wetsel RA, et al. Annu Rev Med. 2011;62:95-105.

Clinical Management of Patients With IPF

Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

Steele MP, Schwartz DA . Annu Rev Med. 2013;64:12.1-12.12

Proposed Pathogenesis of IPF