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Pathobiology of IPF
Glenn D. Rosen, MD
Associate Professor of Medicine
Stanford University School of Medicine
Stanford, California
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.
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
Molecular
Radiographic
Pathologic
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.
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.
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
•
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•
•
•
1.
2.
3.
4.
5.
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.
Biomarker Applications in IPF
Zhang Y, Kaminski N. Curr Opin Pulm Med. 2012;18(5):441-446.
Genetic Changes in Sporadic IPF
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.
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 for
Interstitial Pulmonary Fibrosis
Epithelial
Injury
Inflammation
Fibroblast
Polarization of
Granulation
proliferation
and
immune response
tissue
Failure of
differentiation
formation re-epithelialization
Th1 cytokines
Th2 cytokines
TGF-β
TGF-β activation
activation
Apoptosis
Angiogenesis
ECM deposition
Fibrosis
Selected Recent
Controlled Trials in IPF
Year
Study
Agent
Result
Reference
2005
IFIGENIA
N-acetylcysteine
Pos
Demedts M, et al. NEJM 2005
2009
GIPF-007
IFN-
Neg
King TE Jr, et al. Lancet 2009
2010
Shionogi
Pirfenidone
Neg
Taniguchi H, et al. ERJ 2010
2010
STEP
Sildenafil
Neg
Zisman D, et al. NEJM 2010
2011
BUILD-3
Bosentan
Neg
King TE Jr, et al. AJRCCM 2011
2011
CAPACITY
Pirfenidone
Pos/Neg
Noble PW, et al. Lancet 2011
2011
BIBF-1120
BIBF-1120
Neg
Richeldi L, et al. NEJM 2011
2012
PANTHER
Pred/Aza/NAC
Neg
Raghu G, et al. NEJM 2012
2012
ACE
Warfarin
Neg
Noth I, et al. AJRCCM 2012
2012
IPF
CNTO888
Neg
ClinicalTrials.gov NCT00786201
Adapted from Kevin Brown, MD
Current Drug Trials in IPF
Agent
Target
N
Phase
QAX576
IL-13
40
2
STX-100
Integrin avb6
32
2
Oxidation
500
3
FG-3019
CTGF
84
2
Sirolimus
mTOR
45
N/A
LPA1 Receptor
300
2
LOXL2
48
1
Pirfenidone (ASCEND)
AM152
GS-6624 (AB0024)
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)
CF (N = 3,746)
COPD (N = 8,812)
IPF (N = 4,695)
IPAH (N = 1,065)
Sarcoidosis (N = 597)
Survival (%)
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
25
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
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.
Proposed Pathogenesis of IPF
Steele MP, Schwartz DA . Annu Rev Med. 2013;64:12.1-12.12