Outline Predisposition to Idiopathic Pulmonary What is IPF? - PowerPoint PPT Presentation

11/5/2016 Outline • Predisposition to Idiopathic Pulmonary What is IPF? Fibrosis (IPF) Insights into Pathogenesis – Epidemiology of IPF – Genetic predisposition • Initiation of IPF – Epithelial cell dysfunction Paul Wolters • Telomere dysfunction Professor • Propagation of IPF University of California, San Francisco – Pathologic Matrix IPF: Pathology IPF: Pathology 1

11/5/2016 IPF: Survival Predisposition to IPF: Epidemiology /IPF IPF is a Disease Associated With Aging Risk Factors for IPF • Tobacco smoking • Working in dusty environments • Gastroesophageal reflux disease • Aging • Genetic predisposition Ley, Clin Epidemiol 2013 2

11/5/2016 Prevalence of IPF is Increasing Population is Aging Raghu et al, Lancet Resp Med 2014 Genetics: Dyskeratosis Congenita • Skin hyperpigmentation • Nail dystrophy • Oral leukoplakia Predisposition to IPF: Genetics • Liver cirrhosis • Bone marrow failure • Lung fibrosis Caused by mutations in: TERT, TERC, proteins in shelterin complex 3

11/5/2016 Telomerase Mutations and Lung Genetics: Familial IPF Fibrosis Genes Associated with Familial ILD • Patients with Dyskeratosis Nogee et al, NEJM ‘01 SPA Congenita have mutations Thomas et al, Am J Resp Crit Care Med ‘02 in TERT , TERC, DKC1 and SPC Armanios et al, New Engl J Med ’07 Tsakiri et al, PNAS ‘07 lung fibrosis TERT Alder et al, PNAS ’08 Wang et al, Am J Hum Genet ‘09 • TERT / TERC mutations are TERC Diaz de Leon et al, Plos One ’10 found in 8-15% of patients Kropski et al, Chest 2014 RTEL1 with FPF, 5% with IPF. Stuart et al, Nat Genetics ’15 PARN Cogan et al, Am J Resp Crit Care Med ‘15 Diaz de Leon et al, Plos One ‘ 10 • Lung fibrosis is found in Alder et al, PNAS ‘ 08 ABCA3 40% of patients with Armanios et al, New Engl J Med ‘ 07 TERT/TERC mutations. TINF2 DKC1 Genetics: Sporadic IPF MUC5B Variant • MUC5B: Glycoprotein encoded by the MUC5B gene. • Expressed mostly in distal airways – Increased expression in honeycomb cyst of IPF lung 1616 pts with IPF • Odds ratio for developing disease 4618 controls – Heterozygous (GT)= 6.8-9.0 – Homozygous (TT)= 21-22 • Genetic association replicated in many studies. • Variant causes increased MUC5B expression. Unknown how this contributes to disease pathogenesis. Fingerlin et al, Nat Gen 2013 4

11/5/2016 IPF Genetic Predisposition: Summary Genes Associated with Familial ILD Genes Associated with Sporadic IPF SPA MUC5B SPC DSP TERT TERT Initiation of IPF: TERC TERC Epithelial cell Telomere Dysfunction RTEL1 OBFC1 PARN DPP9 ABCA3 FAM13A TINF2 TOLLIP DKC1 Pulmonary fibrosis genetic studies overwhelmingly implicate epithelial cells and telomere dysfunction in disease process Peripheral Blood Leukocyte Telomeres Telomeres/Telomerase Shorten with Aging • Telomere: Repetitive DNA sequence at end of chromosomes, which protect the end of chromosomes from deterioration. • Maintained by telomerase • Telomeres progressively shorter with each cell division. • Cells with short telomeres either senesce or die. Vaziri et al. AJHG (1995) Cawthon et al. Lancet (2005) 5

11/5/2016 Lung Telomeres Shorten Relatively Peripheral Blood Leukocyte Telomeres Length Predicts IPF Patient Survival More Than other Organs Time to Death Stuart et al, Lancet Resp Med 2014 Gardner et al, J Gerontol Biol Soc 2007 Epithelial Cell Senescence is Unique to Telomeres are Shortened in IPF Type II Cells IPF IPF Normal HP SSc Alder J K et al. PNAS 2008 Kropski et al. Am J Resp Crit Care Med 2015 Wolters, unpublished Disayabutr et al, PLOSONE 2016 6

11/5/2016 Modeling Telomere Dysfunction in Mice • Mouse telomeres are 5-10x longer than Modeling Telomere Dysfunction human telomeres • Deletion of TERT or TERC do not successfully model diseases of telomere dysfunction – Mice become sterile before diseases manifest. Blood 2012 7

11/5/2016 Type II Cell-Specific Telomere Type II Cell-Specific Telomere Dysfunction Causes Lung Fibrosis Dysfunction Causes Lung Fibrosis **p< 0.01 Naikawadi et al, JCI Insight 2016 Naikawadi et al, JCI Insight 2016 Lung Remodeling is Associated with Increased Levels of Active TGF β TRF1 F/F SPC-creTRF1 F/F * Propagation of IPF : Active TGF- β 1 (pg/ml) 50 40 Pathologic Matrix 30 20 10 0 Tamox 3M 8M 8

11/5/2016 IPF Fibroblast Biology Decellularized lung • 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 Booth et al, AJRCCM, 2012 IPF Extracellular Matrix Has a Unique IPF Matrix is Stiffer than Normal Composition Higher in IPF Matrix Lower in IPF Matrix Booth et al, AJRCCM, 2012 Booth et al, AJRCCM, 2012 9

11/5/2016 Fibrotic Matrix Activates a Positive IPF Pathogenesis: Summary Feedback Normal TII Cell TII Cell replication Misfolded protein Infections Telomere shortening Genetic predisposition (SPC, TERT, TERC, MUC5B) Environmental insult, Time/Ageing Critically short telomere’s TII Cell replication Senescent ER Stress AECII turnover apoptosis Telomere Shortening TII Cell Deposition of pathologic Activated fibroblast matrix Myofibroblast differentiation Parker et al JCI 2014 Clinical Relevance: IPF Comorbidities Clinical Relevance: Management • Engage in behaviors that maintain telomere • Family history length • Early Greying (< age 30) of hair may be clue to – Aerobic exercise telomere dysfunction, IPF – De-stress your life, increase social support • Bone marrow abnormalities – Healthy diet, antioxidants, fish oil • Engage in behaviors that limit risk for injury to – Macrocytic anemia – Myelodysplastic syndrome the lung – Avoid pollution • Predisposition to cancer – Vaccinate • Co-morbidity of cirrhosis – No smoking 10