PILOT Slides 2006 Sec01

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Published on February 18, 2008

Author: Demetrio

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Pathogenesis and Pathophysiology of IPF: Bridging the Gap for the Practitioner :  Pathogenesis and Pathophysiology of IPF: Bridging the Gap for the Practitioner Learning Objectives:  Learning Objectives Review and discuss the clinical application of emerging concepts in the pathogenesis of IPF  Define and identify the hallmark histological pattern found in IPF patients Explore the evolution of thought regarding the pathogenesis of IPF Discuss the unpredictable progression of IPF ATS/ERS Classification of Idiopathic Interstitial Pneumonias:  ATS/ERS Classification of Idiopathic Interstitial Pneumonias ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304. Slide4:  Histopathologic Patterns in IIP Adapted from: Thannickal VJ, et al. Ann Rev Med. 2004;55:395-417. - Age Genetic factors Environmental factors Nature of injury Histopathologic Pattern DIP RB - ILD LIP COP NSIP AIP UIP Inflammation Fibrosis LUNG INJURY Slide5:  Current Definition of IPF A distinct type of chronic fibrosing interstitial pneumonia of unknown cause, limited to the lungs, and associated with a surgical lung biopsy showing a histologic pattern of UIP ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664; and 2002;165:277-304. UIP Is the Histologic Hallmark of IPF:  UIP Is the Histologic Hallmark of IPF Diagnostic criteria of UIP: Clear evidence of temporally heterogeneous areas of normal lung, fibroblastic foci, and microscopic honeycombing Recent evidence from patient lung biopsies and lung explant studies suggests the coexistence of UIP with other histopathologic patterns, including NSIP and DIP ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664. Flaherty KR, et al. Am J Respir Crit Care Med. 2001;164:1722-1727. Slide7:  US Demographics Incidence: > 30,000 patients/year Prevalence: > 80,000 current patients Age of onset: 40–70 years Two-thirds > 60 years old at presentation Males > females ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664. Raghu G, et al. Am J Respir Crit Care Med. 2006;174:810-816. Slide8:  Epidemiology of IPF Estimated 89,000 Current Patients in the United States Estimated 34,000 New Patients Per Year in the United States 0 50 100 150 200 250 300 45-54 55-64 65-74 75+ Male Female 0 20 40 60 80 100 120 45-54 55-64 65-74 75+ Male Female Prevalence Incidence Raghu G, et al. Am J Respir Crit Care Med. 2006;174:810-816. Per Hundred Thousand Per Hundred Thousand Slide9:  Potential Risk Factors for IPF Familial Smoking Environmental factors (eg, occupational exposure to wood dust or metal dust) Chronic aspiration associated with gastroesophageal reflux disease (GERD) Infectious agents ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664. Current Hypotheses for the Pathogenesis of IPF:  Current Hypotheses for the Pathogenesis of IPF Inflammatory hypothesis: Fibrosis is preceded and driven by a chronic inflammatory cellular infiltrate/reaction Aberrant wound healing hypothesis: Fibrosis results from abnormal wound healing in response to epithelial injury in the relative absence of inflammation Multiple hit hypothesis: Fibrosis results from dynamic host inflammatory and repair responses to recurrent or persistent lung injury Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758. Raghu G, Chang J. Clin Chest Med. 2004;25:621-636. Selman M, et al. Drugs. 2004;64:405-430. Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417. Inflammatory Hypothesis:  Inflammation causes fibrosis Inflammatory concept was dominant in the 1970s and 1980s IPF results from unremitting inflammatory response to injury that culminates in progressive fibrosis Concept supported by collagen vascular disease and chronic extrinsic hypersensitivity pneumonitis, which are inflammatory processes that lead to fibrosis Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii. Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v. Injury Inflammation Fibrosis Inflammatory Hypothesis Aberrant Wound Healing Hypothesis:  Fibrosis results from an abnormal wound healing response to epithelial injury and activation with a relative absence of inflammation Supporting evidence: Inflammation is not a prominent histopathologic finding in UIP Inflammation is not required for the development of a fibrotic response (animal models) Clinical measurements of inflammation fail to correlate with stage or outcome in IPF Anti-inflammatory therapy does not improve disease outcome Selman M, et al. Ann Intern Med. 2001;134:136-151. Aberrant Wound Healing Hypothesis Slide13:  Multiple microscopic foci of injury occurring over many years Focal (myo)fibroblast proliferation Collagen Deposition Progressive Clinical Course Death Identify source of injury ? Genetic predisposition ? Procoagulant activity Epithelial apoptosis Preserve BM integrity Prevent/interrupt cytokine cascade Myofibroblast apoptosis Antifibrotic agents Characterize/prevent acute exacerbations Prevent infections Thrombotic predisposition CAD PHTN Epithelial damage Wound clot Cellular accumulation Vascular remodeling Multiple Hit Hypothesis Courtesy of Paul W. Noble, MD, and Kevin O. Leslie, MD Support for Multiple Hit Hypothesis:  Support for Multiple Hit Hypothesis Microarray analysis found 4 categories of genes associated with chronic inflammation/immune responses upregulated in fibrotic lung: Smooth muscle markers ECM proteins Pro-inflammatory cytokines and antioxidants Immunoglobulins HRCT study of patients diagnosed with UIP 55% had mediastinal lymphadenopathy Possibly suggests ongoing lymphoproliferative process in response to “antigen” Zuo F, et al. Proc Natl Acad Sci USA. 2002;99:6292-6297. Hunninghake GW, et al. Chest. 2003;124:1215-1223. Slide15:  Epithelial cells Collagen – matrix remodeling Myofibroblast Cell death – impaired reepithelialization Growth factors and other products of epithelial cell injury Evolving Unified Hypothesis: Aberrant Response to Persistent Injury Courtesy of Paul W. Noble, MD, and Victor J. Thannickal, MD. Cell survival – resistance to apoptosis Basement Membrane Damage Oxidative Stress Procoagulant Activity TH2-TH1 Balance Vascular Remodeling Vascular Remodeling:  Aberrant vascular remodeling supports fibrosis and may contribute to increased shunt and hypoxemia Increased angiogenesis results from imbalance of pro-angiogenic chemokines (IL-8, ENA-78) and anti-angiogenic, IFN-inducible chemokines (IP-10) Vascular remodeling leads to anastomoses between the systemic/pulmonary microvasculature, increasing right-to-left shunt, contributing to hypoxemia Chemokine imbalance Increased angiogenesis Fibrosis Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii. Strieter RM, et al. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-69. Vascular Remodeling Aberrant vascular remodeling Vascular Remodeling Is Regulated by Both Positive and Negative Factors:  Vascular Remodeling Is Regulated by Both Positive and Negative Factors Positive Regulators (Angiogenic) Basic fibroblast growth factor (BFGF) Vascular endothelial growth factor (VEGF) Epidermal growth factor (EGF) Endothelin ELR (+) CXC chemokines Negative Regulators (Angiostatic) Courtesy of Robert M. Strieter, MD, FCCP. Angiostatin Endostatin Thrombospondin-1 Tissue inhibitors of metalloproteases (TIMPs) IFN-inducible ELR (-) CXC chemokines Clinical Progression of IPF:  Clinical Progression of IPF Traditional view: Slow and linear decline in respiratory function ultimately leads to respiratory failure and death Emerging paradigm: Stepwise progression Periods of relative stability may be interrupted by acute episodes of worsening lung function that may result in death Noble PW. Am J Respir Cell Mol Biol. 2003;29:S27-S31. King TE, et al. Am J Respir Crit Care Med. 2001;164:1025-1032. Raghu G, et al. N Engl J Med. 2004;350:125-133. Clinical Progression of IPF (cont):  Clinical Progression of IPF (cont) Emerging evidence: Risk of death is similar across various degrees of disease severity Question of physiologic measures as predictors of mortality Acute exacerbations–Nearly half of deaths in a study conducted by Raghu et al occurred prior to physiologic evidence of disease progression. Clinical measures of stability of lung function do not necessarily reflect disease stability Evidence of improved survival in the absence of any effect on pulmonary function Noble PW. Am J Respir Cell Mol Biol. 2003;29:S27-S31. King TE, et al. Am J Respir Crit Care Med. 2001;164:1025-1032. Raghu G, et al. N Engl J Med. 2004;350:125-133. Slide20:  50% Years Respiratory Function/Symptoms 1 2 3 Step Theory of UIP/IPF Progression Progression of IPF: Acute Exacerbation vs Slow Decline FVC 0 4 = events Adapted from: Noble PW. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S27-S31. = Acute exacerbation Potential Strategies and Targets of Therapeutic Intervention:  Potential Strategies and Targets of Therapeutic Intervention Take Home Messages :  Take Home Messages UIP may coexist with other histopathologic patterns in individual patients The role of inflammation in IPF remains unclear The pathogenesis of IPF may involve “multiple hits” that perpetuate a cycle of recurrent lung injury and dysregulated host tissue repair The rate of progression in IPF is unpredictable: rapid declines related to acute exacerbations can occur following periods of relative stability

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