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

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.

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

Radiographic
Molecular
Pathologic
Clinical

•
• 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.

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

Critical Role for Transforming
Growth Factor-
 in Fibrosis
• Delivering active TGFβ by gene therapy causes tissue fibrosis
• Anti-TGFβ therapies (antibodies, IFN-g, pirfenidone, decorin) inhibit fibrosis in animal models and are in clinical trials
• TGFβ directly stimulates matrix production by fibroblasts and inhibits matrix degradation
• TGFβ induces epithelial mesenchymal transition
(EMT)
• TGFβ 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.

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

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.

• 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.

• Matrix Metallo-Proteases (MMP1/MMP3/MMP7) 1
• Surfactant proteins A & D 2 , KL-6 3
• CCL2/CCL18, TGFβ-1 4
• 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.

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

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

Telomerase-Normal Function the 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.

• 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.

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

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

• 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.

Epithelial
Injury
New Paradigm for
Interstitial Pulmonary Fibrosis
Inflammation
Polarization of immune response
Fibroblast proliferation and differentiation
Granulation tissue formation
Failure of re-epithelialization
Th1 cytokines
Th2 cytokines
TGFβ activation
Apoptosis
Angiogenesis
ECM deposition
Fibrosis

Year
2005
2009
2010
2010
2011
2011
2011
2012
2012
2012
Selected Recent
Controlled Trials in IPF
Study Agent
IFIGENIA N-acetylcysteine
GIPF-007 IFN-

Pirfenidone Shionogi
STEP
BUILD-3
Sildenafil
Bosentan
CAPACITY Pirfenidone
BIBF-1120 BIBF-1120
PANTHER Pred/Aza/NAC
ACE
IPF
Warfarin
CNTO888
Result
Pos
Neg
Neg
Neg
Neg
Pos/Neg
Neg
Neg
Neg
Neg
Reference
Demedts M, et al. NEJM 2005
King TE Jr, et al . Lancet 2009
Taniguchi H , et al. ERJ 2010
Zisman D, et al. NEJM 2010
King TE Jr, et al. AJRCCM 2011
Noble PW, et al. Lancet 2011
Richeldi L, et al. NEJM 2011
Raghu G, et al. NEJM 2012
Noth I, et al. AJRCCM 2012
ClinicalTrials.gov NCT00786201
Adapted from Kevin Brown, MD

Agent
QAX576
STX-100
Pirfenidone (ASCEND)
FG-3019
Sirolimus
AM152
GS-6624 (AB0024)
Target
IL-13
Integrin avb6
Oxidation
CTGF mTOR
LPA1 Receptor
LOXL2
N
40
32
500
84
45
300
48
Phase
2
2
3
2
N/A
2
1 http://www.clinicaltrials.gov. Accessed October 2012.

Adult Lung Transplantation
Kaplan-Meier Survival By Diagnosis (Transplants: January 1990 –June 2007)
100
Alpha-1 (N = 2,085)
IPF (N = 4,695)
CF (N = 3,746)
IPAH (N = 1,065)
COPD (N = 8,812)
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
50
25
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
0
0 1 2 3 4 5 6
Years
Christie JD, et al. J Heart Lung Transplant.
2009;28:1031-1049.
7 8 9 10 11 12

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