Pathology Seminar Series April 24, 2012 Stephanie Schutte, MD
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1 Pathology Seminar Series April 24, 2012 Stephanie Schutte, MD
2 Etiology and Pathogenesis Epidemiology Clinical features Risk factors Radiologic features Radiologic progression IPF Acute exacerbation Gross pathology Genomic Approach Microscopic pathology Leslie K. Arch Pathol Lab Med. 2011
3 IPF Review Unrelenting accumulation of myofibroblasts and deposition of collagen Histology: UIP pattern, advanced fibrosis with destruction of lung architecture, honeycombing The fibroblastic foci is an area of major study New focus on the epithelialmesenchymal border
4 IPF - Mechanism of injury A shift: From inflammation invariably leading to fibrosis To repeated epithelial injury and aberrant wound healing leads to fibroblast/myofibroblast accumulation Why the change? Anti-inflammatory and immune modulatory therapy isn t working Both epithelial cells and fibroblasts undergo distinct phenotypic changes
5 Normal response to damage Alveolar epithelial cells: proliferate and produce inflammatory signals TGF-β, PDGF, EGF, and FGF-2 Fibroblasts: respond to epithelial cell signals Activate and differentiate into myofibroblasts Myofibroblasts: secrete collagens and extracellular matrix proteins A second source of myofibroblasts? EMT
6 Epithelial-mesenchymal transition (EMT) Polarized epithelial cell, which normally interacts with a basement membrane undergoes biochemical changes that enable it to assume a mesenchymal cell phenotype New phenotype includes enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of extracellular matrix components First recognized as a feature of embryogenesis Known to play a role in cancer metastasis
7 Epithelial-Mesenchymal transition (EMT) Three biologic settings in which this occurs: EMT during implantation, embryogenesis, and organ development EMT associated with cancer progression and metastasis EMT associated with tissue regeneration and organ fibrosis
8 EMT associated with organ fibrosis Inflammatory cells and fibroblast generate signalling molecules, which initiate EMT Induce basement membrane damage, allowing epithelial cells to migrate into the interstitium Growth factors and other molecules in the interstitium complete the transition
9 EMT associated with organ fibrosis 12% of fibroblasts are from bone marrow 30% can arise via local EMT involving epithelial cells under inflammatory stress 35% are from EndMT Proliferation of the resident fibroblasts Other still unidentified sources. Different sources of fibroblasts in organ fibrosis.
10 What goes wrong in IPF? Normal wound healing signals are present that terminate the process IPF no termination signals Alveolar cells that have undergone EMT do not properly repair alveolar lining Fibroblast accumulation and collagen deposition continues IPF studies: why does the process fail to terminate?
11 Evolving Genomic Approaches to Idiopathic Pulmonary Fibrosis: Moving Beyond Genes. Daniel Kass, MD and Naftali Kaminski, MD Clin Transl Sci October; 4(5):
12 Objectives What are the sources of genomic data in IPF? Do genomic approaches provide clinically relevant diagnostic information on IPF? Do genomic approaches provide clinically relevant prognostic information on IPF How has genomic research enhanced our understanding of the pathogenesis of IPF? What is the state of epigenomic research in IPF? What is the future of genomic research in IPF?
13 Sources of genomic data Lung tissue from patients Biopsy Explant Autopsy Controls Surrogate tissues Cultured fibroblasts Bronchoalveolar lavage Peripheral blood Fibrocytes
14 Lung tissue from patients Biopsy Transbronchial biopsies Wedge biopsies Explants Numbers? Autopsy Delay to autopsy damages tissue warm or rush autopsies Control lung tissue for comparison Normal section from cancer case Rejected cadaveric donors Granuloma or scar biopsy
15 Surrogate tissues Cultured fibroblasts Cells grown under a variety of conditions and in response to various stimuli BAL gene profile of inflammatory cells Peripheral blood mononuclear cells Gene expression of mononuclear cells
16 Surrogate tissues Fibrocytes Identified in 1994, likely bone-marrow derived collagen-producing cells Circulate in the peripheral blood Migrate to sites of injury and differentiate into fibroblast-like cells Purified from PB and analyzed Express collagen-1, CD45, CD34 TGF-β stimulates them to express α-smooth muscle actin
17 Fibrocyte counts Moeller et al. studied fibroblasts as a prognostic marker Threefold increase in circulating fibrocytes in stable IPF as compared to controls Significant increase above baseline counts during an acute exacerbation No significant fibrocyte counte difference between ARDS and normal
18 Fibrocyte counts Higher fibrocyte counts correlated with dramatically decreased survival (7 months v. 27 months) Other clinical parameters did not correlate with survival
19 Objectives What are the sources of genomic data in IPF? Do genomic approaches provide clinically relevant diagnostic information on IPF? Do genomic approaches provide clinically relevant prognostic information on IPF How has genomic research enhanced our understanding of the pathogenesis of IPF? What is the state of epigenomic research in IPF? What is the future of genomic research in IPF?
20 Genomic Profiling Genomic profile: Information about all the genes in an organism, including variations, gene expression, and the way those genes interact with each other and with the environment Genotyping & Genomic Profiling Techniques Single nucleotide polymorphism Genotyping Copy Number Variation Array comparative genomic hybridization Amplified length polymorphism, Restriction fragment length polymorphism, Single strand confirmation polymorphism High Resolution Melting (HRM) Analysis TaqMan Mutation Detection Assays Microsatellite Analysis In Situ Hybridization (ISH) st microarray experiments comparing IPF to uninjured controls were performed
21 Diagnostic information How is the diagnosis of IPF made? Gold standard: wedge biopsy of lung Clinical/radiologic correlation is important Diagnosis of exclusion What if histopathology and clinical correlation fails to make the diagnosis? Consider a genomic approach Is IPF a unique disease with a unique genomic profile? Can we then use this profile to make the diagnosis of IPF?
22 Diagnostics Selman et al. Study Compared lung samples of patients with IPF, hypersensitivity pneumonitis (HP), and nonspecific interstitial pneumonia (NSIP) using custom oligonucleotide microarrays Results: what genes are expressed? IPF tissue remodeling, epithelial and myofibroblast genes HP inflammation, T-cell activation, immune responses NSIP most didn t classify as IPF or HP (has its own distinct gene signature?)
23 Conclusions - IPF lungs do not exhibit typical inflammatory patterns, instead it is characterized by genes involved in active tissue remodeling A. Matrix metalloproteinase-1 B. IGFBP-4 C. N-cadherin Note expression in epithelial cells.
24 Diagnostics Hsu et al. Genomic patterns in IPF and systemic sclerosis related pulmonary fibrosis (SSc-PF) Results 70% of genes that distinguish IPF and SSc-PF from normal lung are shared Conclusions Clinically unique diseases with similar genomic profiles Only a small group of genes differentiates one from the other
25 A. Microarray analysis showing genes that are upregulated and downregulated B. Cluster patterns: 1. Genes that are upregulated in both SSc and IPF 2. Genes that are upregulated in both SSC-PF and IPF 3. Genes that are downregulated in both SSc-PF and IPF 4. Genes that are downregulated in both SSc and IPF C. Venn diagrams showing numbers of unique and shared genes.
26 Diagnostics future considerations Can a particular gene pattern diagnose UIP or HP or NSIP or SSc when histology and clinical criteria can not? Can gene expression identify patients who will respond to immunosuppressive therapy?
27 Objectives What are the sources of genomic data in IPF? Do genomic approaches provide clinically relevant diagnostic information on IPF? Do genomic approaches provide clinically relevant prognostic information on IPF How has genomic research enhanced our understanding of the pathogenesis of IPF? What is the state of epigenomic research in IPF? What is the future of genomic research in IPF?
28 Prognostic information Clinical predictors of increased mortality Rate of decline in spirometry Degree of exercise limitation Presence of pulmonary hypertension An acute exacerbation Genomic approaches compare those who have increased predictors to those who don t
29 Prognostics Rajkumar et al. compared patients with idiopathic pulmonary artery HTN (PAH) to patients with HTN secondary to IPF Results IPF patients with pulmonary HTN had distinctive gene signatures as compared to patients with PAH and normal subjects Genes that function in TGF-β and platelet derived growth factor signaling pathways were enriched in IPF patients with pulmonary HTN
30 Prognostics Boon et al. compared gene expression profiles of patients with stable disease and rapidly progressing disease SAGE technique (Serial Analysis of Gene Expression) Uncovered gene transcripts that distinguished stable versus progressive IPF 102 up-regulated transcripts (progressive group) 89 down-regulated transcripts (progressive group) Plunc (palate, lung and nasal epithelium carcinoma associated protein) Not previously implicated in IPF
31 Prognostics Plunc staining in IPF (bronchial columnar cells in areas of honeycombing) as compared to normal control (no Plunc expression)
32 Prognostics Selman et al. analyzed patients with a rapid course of IPF and identified a distinct molecular signature rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells 3 rapid progressors show staining for prominin-1/ CD133 D & E slow progressor and normal Note the epithelial staining
33 Objectives What are the sources of genomic data in IPF? Do genomic approaches provide clinically relevant diagnostic information on IPF? Do genomic approaches provide clinically relevant prognostic information on IPF How has genomic research enhanced our understanding of the pathogenesis of IPF? What is the state of epigenomic research in IPF? What is the future of genomic research in IPF?
34 Pathogenesis Most IPF studies have focused on single genes to determine their relevance to IPF Looking to identify potential drug targets Identify factors that promote fibroblast accumulation in the lung Why do they have increased proliferation and decreased apoptosis?
35 Pathogensis Matrilysin (matrix metalloproteinase 7, MMP-7) Early IPF studies using gene expression profiling (Zuo et al.) Enriched expression of MMP-7 MMP-7 -/- mice were protected from bleomycin induced PF Mechanism? A possible biomarker? Twist1 Plays a role in tumor metastasis and epithelial-mesenchymal transition Necessary for fibroblast survival in vitro Mediator of EMT in pulmonary fibrosis
36 Pathogenesis Osteopontin Increases proliferation and migration in human lung fibroblasts and Type II alveolar epithelial cells Increased gene expression has been confirmed by real-time PCR in patients with UIP (as has increased MMP7) Pigment epithelium-derived factor Present in fibroblastic foci of IPF Induced by TGF-β1
37 Pathogenesis cell biology IPF fibroblasts have pro-proliferative and anti-apoptotic properties Why? Increased Wnt5a expression, acts as a proproliferative and anti-apoptotic signal in human lung fibroblasts React differently than normal lung fibroblasts to TGF-β1 stimulation
38 Pathogenesis global gene expression patterns Significantly increased expression (in IPF) of genes that are associated with lung development Wnt and TGF-β signalling pathways A pathologic repetition of embryonic development?
39 TGF-β and PTEN TGF-β: controls cell growth, cell proliferation, cell differentiation and apoptosis PTEN inhibits cell migration, promotes cellular apoptosis, and inhibits cell growth Fibroblasts of IPF patients have been shown to diminished PTEN expression
40 PTEN & PS6 expression Evaluate PTEN & PS6 expression in IPF lungs vs. lungs with non-progressive fibrosis vs. normal Image 1 Normal lung: H&E, PS6, PTEN, and SMA (left to right). Normal airway shows positivity for SMA (smooth muscle), PTEN (epithelium), and PS6 (epithelium).
41 PTEN & PS6 expression Subpleural fibrosis (non-progressive) Image 2 Reactive pleuritis with fibrosis: H&E, PS6, PTEN, and SMA (left to right). In these areas of subpleural fibrosis, SMA, PTEN, and PS6 expression is strong and coexpressed. In the normal pleura there is no SMA or PTEN staining.
42 PTEN & PS6 expression Fibroblastic foci of IPF Image 3- Idiopathic pulmonary fibrosis: H&E, PS6, PTEN, and SMA (left to right). The fibroblastic foci (arrows) shows SMA positivity and loss of PTEN/ PS6. The normal epithelium (lower aspect) maintains PTEN/PS6 expression.
43 Results In the non-progressive fibrosis cases, SMA, PTEN and PS6 expression were all strongly positive in subpleural areas of fibrosis and also areas of organization. In the IPF cases, SMA showed strong positivity in fibroblastic foci and honeycomb areas while PTEN and PS6 expression were decreased. Interestingly, the epithelium overlying the fibroblastic foci was greatly attenuated with decrease in PTEN and PS6 expression.
44 TGF-β and PTEN TGF-β: controls cell growth, cell proliferation, cell differentiation and apoptosis PTEN inhibits cell migration, promotes cellular apoptosis, and inhibits cell growth Fibroblasts of IPF patients have been shown to diminished PTEN expression
45 Conclusions In IPF, in areas of fibroblastic foci and honeycombing, SMA expression increases while PTEN and PS6 decrease. In reactive pleuritis with fibrosis, SMA, PTEN and PS6 are strongly coexpressed. PTEN repression contributes to myofibroblastic differentiation, proliferation and continued matrix deposition in IPF and may be a factor in the progression of the disease. Because non-progressive scarring can show variable PTEN expression, other pathways may also be active in the progressive injury of IPF.
46 Objectives What are the sources of genomic data in IPF? Do genomic approaches provide clinically relevant diagnostic information on IPF? Do genomic approaches provide clinically relevant prognostic information on IPF How has genomic research enhanced our understanding of the pathogenesis of IPF? What is the state of epigenomic research in IPF? What is the future of genomic research in IPF?
47 Epigenomic research Epigenetics regulation of phenotype or gene expression by changes independent of the underlying DNA sequence Uses many of the same techniques as genomic studies Methylation Early studies: changes in global methylation patterns in IPF tissue and fibroblasts MicroRNA recruitment
48 Epigenomics - microrna microrna let7d Decreased in IPF Binds to a TGF-β intermediate Inhibition of let7d increased collagen gene expression and EMT in mice microrna 21 Increased in IPF and 1 lung fibroblasts stimulated with TGF-β Suppression of mir-21 attenuated bleomycininduced lung injury in mice
49 Objectives What are the sources of genomic data in IPF? Do genomic approaches provide clinically relevant diagnostic information on IPF? Do genomic approaches provide clinically relevant prognostic information on IPF How has genomic research enhanced our understanding of the pathogenesis of IPF? What is the state of epigenomic research in IPF? What is the future of genomic research in IPF?
50 The future of genomic research Obstacles to overcome Limited availability of tissues Data sharing across centers Must replicate observations independently Training for new genomic researches NIH funded studies Created a repository of lung tissue, blood, imaging and clinical data of IPF patients Multidisciplinary teams are assembling databases of genomic data on IPF Ensure adequate funding for training of new researches
51 The future of genomic research Paradigm shift from single-gene approach to a global genome approach Provides more insight in the complex pathogenesis of IPF Provide a better working model of how abnormal organ phenotypes are maintained over time, years after the inciting injury Impact for patients A few clinical trials involving newer molecular targets, including TGF-β No trials yet involving MMP-7, Twist1, IGFBP, and microrna
52 Conclusion Genomic research has had an impact on our understanding of IPF Genomic profiling has identified several new molecules involved in the mechanism of IPF Genomic profiling has demonstrated that gene signatures may be able to predict the rate of IPF progression
53 References Dr. Jagirdar Leslie K. Idiopathic Pulmonary Fibrosis May Be a Disease of Recurrent, Tractional Injury to the Periphery of the Aging Lung. A Unifying Hypothesis Regarding Etiology and Pathologenesis. Arch Pathol Lab Med. October Kass D, Kaminski N. Evolving Genomic Approaches to Idiopathic Pulmonary Fibrosis: Moving Beyond Genes. Coin Transl Sci October; 4(5): Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J. 2007; 30: Moeller A, Gilpin SD, Ask K, Cox G, Cook D, Gauldie J, Margetts PJ, Farkas L, Dobranowski J, Boylan C, et al. Circulating fibrocyes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009; 179: Selman M, Pardo A, Barrera L, Es-trada A, Watson S, Wilson K, Aziz N, Kaminski N, Zlotnik A. Gene Expresion Profiles Distinguish Idiopathic Pulmonary Fibrosis from Hypersentsitivity Pneumonitis. Am J Respir Crit Care Med. 2006; 173: Boon K, Bailey N, Yang J, Steel M, Groshong S, Kervitsky D, Brown K, Schwarz M, Schwartz D. Molecular Phenotypes Distinguish Patients with Relatively Stable from Progressive Idiopathic Pulmonary Fibrosis. PLoS One. 2009; 4:e5134. Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA. Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum March;63(3): Rajkumar R, Knoishi K, Richards TJ, Ishizawar DC, Wiechert AC, Kaminski N, Ahmad F. Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hyptertension. Am J physiol Heart Circ Physiol April;298(4):H Kalluri R, Wienberg R. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6): Profiling.htm White E, Atrasz R, Hu B, Phan S, Stamblic V, Mak T, Hogaboam C, Flaherty K, Martinez F, Kontos C, Toews G. Negative Regulation of Myofibroblast Differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome 10). Am J Respir Crit Care Med. Vol 173. pp Sawyers C. The Cancer Biomarker Problem. Nature 452, (3 April 2008)
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