11/5/2016 1 What is IPF? Insights into Pathogenesis Paul Wolters Professor University of California, San Francisco Outline • Predisposition to Idiopathic Pulmonary Fibrosis (IPF) – Epidemiology of IPF – Genetic predisposition • Initiation of IPF – Epithelial cell dysfunction • Telomere dysfunction • Propagation of IPF – Pathologic Matrix IPF: Pathology IPF: Pathology
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11/5/2016
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What is IPF?Insights into Pathogenesis
Paul WoltersProfessor
University of California, San Francisco
Outline• Predisposition to Idiopathic Pulmonary
Fibrosis (IPF)– Epidemiology of IPF– Genetic predisposition
• Initiation of IPF– Epithelial cell dysfunction
• Telomere dysfunction• Propagation of IPF
– Pathologic Matrix
IPF: Pathology IPF: Pathology
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IPF: Survival
/IPF
Predisposition to IPF: Epidemiology
Risk Factors for IPF
• Tobacco smoking• Working in dusty environments• Gastroesophageal reflux disease• Aging• Genetic predisposition
IPF is a Disease Associated With Aging
Ley, Clin Epidemiol 2013
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Population is Aging Prevalence of IPF is Increasing
Raghu et al, Lancet Resp Med 2014
Predisposition to IPF: Genetics
Genetics: Dyskeratosis Congenita• Skin hyperpigmentation• Nail dystrophy• Oral leukoplakia• Liver cirrhosis• Bone marrow failure• Lung fibrosis
Caused by mutations in:TERT, TERC, proteins in shelterin complex
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Telomerase Mutations and Lung Fibrosis
• Patients with Dyskeratosis Congenita have mutations in TERT, TERC, DKC1 and lung fibrosis
• TERT/TERC mutations are found in 8-15% of patients with FPF, 5% with IPF.
• Lung fibrosis is found in 40% of patients with TERT/TERC mutations. Diaz de Leon et al, Plos One ‘10
Alder et al, PNAS ‘08Armanios et al, New Engl J Med ‘07
Genes Associated with Familial ILDSPASPC
TERTTERCRTEL1PARN
ABCA3TINF2DKC1
Genetics: Familial IPF
Nogee et al, NEJM ‘01Thomas et al, Am J Resp Crit Care Med ‘02Armanios et al, New Engl J Med ’07Tsakiri et al, PNAS ‘07Alder et al, PNAS ’08Wang et al, Am J Hum Genet ‘09Diaz de Leon et al, Plos One ’10Kropski et al, Chest 2014Stuart et al, Nat Genetics ’15Cogan et al, Am J Resp Crit Care Med ‘15
Genetics: Sporadic IPF
Fingerlin et al, Nat Gen 2013
1616 pts with IPF
4618 controls
MUC5B Variant • MUC5B: Glycoprotein encoded by the MUC5B gene.• Expressed mostly in distal airways
– Increased expression in honeycomb cyst of IPF lung• Odds ratio for developing disease
Alder J K et al. PNAS 2008Kropski et al. Am J Resp Crit Care Med 2015Wolters, unpublished
Epithelial Cell Senescence is Unique to IPF
IPF Normal
HP SSc
Disayabutr et al, PLOSONE 2016
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Modeling Telomere Dysfunction
Modeling Telomere Dysfunction in Mice
• Mouse telomeres are 5-10x longer than human telomeres
• Deletion of TERT or TERC do not successfully model diseases of telomere dysfunction– Mice become sterile before diseases manifest.
Blood 2012
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Type II Cell-Specific Telomere Dysfunction Causes Lung Fibrosis
Naikawadi et al, JCI Insight 2016
Type II Cell-Specific Telomere Dysfunction Causes Lung Fibrosis
**p< 0.01
Naikawadi et al, JCI Insight 2016
0
10
20
30
40
50
TRF1F/F
SPC-creTRF1F/F
*
3M 8MTamox
Act
ive
TG
F- β1
(pg
/ml)
Lung Remodeling is Associated with Increased Levels of Active TGFβ
Propagation of IPF :Pathologic Matrix
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IPF Fibroblast Biology• IPF fibroblasts are different from “normal” fibroblasts.
– Resistant to apoptosis– Make more collagen– More invasive
• Fibroblast phenotype differs when cultured on matrix of different stiffness (Young’s elastic modulus).– Stiffness of lung: 1 kPa– Stiffness of plastic: 2-4 GPa
• Fibroblasts alter phenotype when cultured on matrix derived from IPF lung vs. normal lung
Decellularized lung
Booth et al, AJRCCM, 2012
IPF Extracellular Matrix Has a Unique Composition
Higher in IPF Matrix Lower in IPF Matrix
Booth et al, AJRCCM, 2012
IPF Matrix is Stiffer than Normal
Booth et al, AJRCCM, 2012
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Fibrotic Matrix Activates a Positive Feedback
Parker et al JCI 2014
IPF Pathogenesis: Summary
ER Stress AECII turnover
Normal TII Cell TII Cell replicationTelomere shortening