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