1. Pathogenesis and Pathophysiology of IPF: Bridging the Gap for the Practitioner

2. 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
Learning Objectives
This slide section will review and discuss the clinical application of emerging concepts in the pathogenesis of IPF. This will include:
Defining and identifying the hallmark histological pattern found in IPF patients
Exploring the evolution of thought regarding the pathogenesis of IPF
Discussing the unpredictable progression of IPF

3. ATS/ERS Classification of Idiopathic Interstitial Pneumonias
Histologic Pattern
Clinical/Radiologic/Pathologic Diagnosis
Usual interstitial pneumonia
Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis
Nonspecific interstitial pneumonia
Organizing pneumonia
Cryptogenic organizing pneumonia
Diffuse alveolar damage
Acute interstitial pneumonia
Respiratory bronchiolitis
Respiratory bronchiolitis interstitial lung disease
Desquamative interstitial pneumonia
Lymphoid interstitial pneumonia
ATS/ERS Classification of Idiopathic Interstitial Pneumonias
A joint statement of the American Thoracic Society (ATS) and European Respiratory Society (ERS) was produced to standardize the classification of the idiopathic interstitial pneumonias (IIPs) and to establish a uniform set of definitions and criteria for the diagnosis of IIPs. The classification of IIPs included 7 clinical/radiologic/pathologic entities that are listed in this slide in order of relative frequency:
IPF/cryptogenic fibrosing alveolitis
Nonspecific interstitial pneumonia
Cryptogenic organizing pneumonia
Acute interstitial pneumonia
Respiratory bronchiolitis interstitial lung disease
Desquamative interstitial pneumonia
Lymphoid interstitial pneumonia
To clarify the relationship between the pathologic and clinical terms that have been used for these entities, the new classification defines a set of histologic patterns that provides the basis for the final clinical/radiologic/pathologic diagnosis.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;166:
ATS/ERS. Am J Respir Crit Care Med. 2002;165:

4. Histopathologic Patterns in IIP
LUNG INJURY
Age
Genetic factors
Environmental factors
Nature of injury
Histopathologic Pattern
Histopathologic Patterns in IIP
The histopathologic patterns of the various types of IIP represent a spectrum of tissue reactions with varying degrees of inflammation and fibrosis. The histopathologic pattern is influenced by a number of factors including age, genetic susceptibility, environmental factors, and the nature of the injurious agent.
DIP = desquamative interstitial pneumonia
RB-ILD = respiratory bronchiolitis-associated interstitial lung disease
LIP = lymphocytic interstitial pneumonia
COP = cryptogenic organizing pneumonia
NSIP = nonspecific interstitial pneumonia
AIP = acute interstitial pneumonia
UIP = usual interstitial pneumonia (including IPF)
Thannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Ann Rev Med. 2004;55:
DIP RB -
ILD
LIP
COP
NSIP
AIP
UIP
Inflammation
Fibrosis
Adapted from: Thannickal VJ, et al. Ann Rev Med. 2004;55: -

5. 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
Current Definition of IPF
According to the ATS/ERS Consensus Statement, IPF is currently defined as 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 usual interstitial pneumonia (UIP).
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;166:
ATS/ERS. Am J Respir Crit Care Med. 2000;161: ; and 2002;165:

6. 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
UIP Is the Histologic Hallmark of IPF
According to the ATS/ERS Consensus Statement, UIP is the histologic pattern that identifies patients with IPF.
The diagnostic criteria of UIP include clear evidence of temporally heterogeneous areas of normal lung, fibroblastic foci, and microscopic honeycombing with a subpleural/peripheral-lobular distribution.
Recent evidence from patient lung biopsies and lung explant studies suggests the coexistence of UIP with other histopathologic patterns, including NSIP and DIP.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2000;161:
Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164:
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
Flaherty KR, et al. Am J Respir Crit Care Med. 2001;164:

7. 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
US Demographics
Currently, more than 80,000 adults have IPF in the US, and more than 30,000 new cases are diagnosed each year. Patients with IPF are generally middle aged, with most patients between 40 and 70 years of age at onset. Approximately two-thirds of patients are over 60 years old at presentation, with a mean age of 66 years at diagnosis. The disease is more common in males than in females, but there is no evidence for racial or ethnic predilection.
In a recent analysis using age, medical claim, and differential diagnosis criteria, Raghu and colleagues estimate a US prevalence of 89,000 cases and a US incidence of 34,000 new cases per year.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2000;161:
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:
ATS/ERS. Am J Respir Crit Care Med. 2000;161:
Raghu G, et al. Am J Respir Crit Care Med. 2006;174:

8. Epidemiology of IPF Incidence Prevalence
120
300
100
250
Male
Male 80
Female
200
Female
Per Hundred Thousand
Per Hundred Thousand 60
150 40
100 20 50
45-54
55-64
65-74
75+
45-54
55-64
65-74
75+
Epidemiology of IPF
This slide reiterates that the incidence and prevalence of IPF increases with age, and that the disease is more common in men than women. Because IPF is a chronic disease that is almost uniformly fatal, the ratio of the prevalence to the incidence can provide a crude indication of the duration of survival after diagnosis of approximately 2.5–3 years. This estimate is consistent with the current estimate of median survival of 3–5 years.
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:
Estimated 34,000 New Patients Per Year in the United States
Estimated 89,000 Current Patients in the United States
Raghu G, et al. Am J Respir Crit Care Med. 2006;174:

9. 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
Potential Risk Factors for IPF
A number of potential risk factors for the development of IPF have been identified. Hereditary factors may contribute, although no specific genetic markers have been identified. Cigarette smoking is also a risk factor, with odds ratios from various geographic regions ranging from 1.6 to 2.9 in ever-smokers. Various environmental exposures in rural/agricultural area and in urban and manufacturing settings have been linked to IPF, with metal dust and wood dust exposure showing the most prominent associations. Chronic aspiration secondary to gastroesophageal reflux disease (GERD) is common in patients with IPF, although a causative link has not been established. Several viruses (eg, Epstein-Barr virus, Cytomegalovirus, hepatitis C) have been associated with IPF; however, there is no clear evidence for a viral etiology.
American Thoracic Society. American Thoracic Society/European Respiratory Society International Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2000;161:
ATS/ERS. Am J Respir Crit Care Med. 2000;161:

10. 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
Current Hypotheses for the Pathogenesis of IPF
Although the pathogenesis of IPF is unclear, several hypotheses are currently being studied:
Inflammation hypothesis: Fibrosis is driven by a chronic inflammatory cellular infiltrate/reaction in which inflammation precedes the development of fibrosis
Aberrant wound healing hypothesis: Fibrosis results from abnormal wound healing in response to epithelial injury and 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. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25:
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25:
Selman M, Thannickal VJ, Pardo A, et al. Idiopathic pulmonary fibrosis; pathogenesis and therapeutic approaches. Drugs. 2004;64:
Thannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:
Noble PW, Homer RJ. Clin Chest Med. 2004;25:
Raghu G, Chang J. Clin Chest Med. 2004;25:
Selman M, et al. Drugs. 2004;64:
Thannickal VJ, et al. Annu Rev Med. 2004;55:

11. 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
Injury
Fibrosis
Inflammatory Hypothesis
In the 1970s and 1980s, the inflammatory concept was dominant. According to this hypothesis, IPF results from an unremitting inflammatory response to injury that culminates in progressive fibrosis. The concept is supported by collagen vascular disease and chronic extrinsic hypersensitivity pneumonitis, which are inflammatory processes that lead to fibrosis. This hypothesis is also supported by the observation that inflammatory cells (ie, neutrophils, eosinophils) are increased in bronchoalveolar lavage fluid from patients with IPF.
However, the role of inflammation remains controversial. The lack of efficacy of corticosteroids and other immunomodulators for IPF indicates that inflammation may not be the dominant mechanism at the time of therapy. Inflammation may be a result rather than a cause of fibrosis.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25:
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25:
Inflammation
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Clin Chest Med. 2004;25: , v.

12. 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
Aberrant Wound Healing Hypothesis
In contrast to the inflammatory hypothesis, the aberrant wound healing hypothesis posits that fibrosis in IPF results from epithelial injury and abnormal wound healing in the relative absence of chronic inflammation. Proponents of this hypothesis cite the following observations as evidence that inflammation is not a primary factor in the development of IPF:
Inflammation is not a prominent histopathologic finding in UIP
Animal models have demonstrated that inflammation is not required for the development of a fibrotic response
Clinical measurements of inflammation fail to correlate with stage or outcome in IPF
Antiinflammatory therapy does not improve IPF disease outcome, in contrast to other interstitial lung diseases such as:
– Sarcoidosis
– Hypersensitivity pneumonitis
– Nonspecific interstitial pneumonia
– Desquamative interstitial pneumonia
Selman M, King TE Jr, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:
Selman M, et al. Ann Intern Med. 2001;134:

13. Multiple Hit Hypothesis
Multiple microscopic foci of injury occurring over many years
Epithelial damage
Wound clot
Cellular accumulation
Identify source of injury
? Genetic predisposition
? Procoagulant activity
Epithelial apoptosis
Preserve BM integrity
Prevent/interrupt
cytokine cascade
Myofibroblast apoptosis
Focal (myo)fibroblast proliferation
Vascular remodeling
Antifibrotic agents
Collagen Deposition
Characterize/prevent
acute exacerbations
Prevent infections
Thrombotic predisposition
CAD
PHTN
Multiple Hit Hypothesis
This slide schematically depicts the pathogenic events associated with the multiple hit hypothesis. According to this hypothesis, multiple micro-injuries damage and activate alveolar epithelial cells. The microscopic foci of injury accumulate over many years, producing epithelial damage that is confined to small foci of actively proliferating myofibroblasts that are widely scattered. Intra-alveolar and interstitial myofibroblasts secrete extracellular matrix proteins, mainly collagens. Deposition of the extracellular matrix results in the development of clinical symptoms and a worsening disease course.
Noble PW, Homer RJ. Back to the future: historical perspective on the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2005;33:
Selman M, King TE Jr, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:
Progressive Clinical Course
Death
Courtesy of Paul W. Noble, MD, and Kevin O. Leslie, MD

14. 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”
Support for Multiple Hit Hypothesis
Two recent studies have provided evidence to support the multiple hit hypothesis.
Zuo and colleagues analyzed gene expression in lung tissue from patients with IPF. Microarray analysis found 4 categories of genes associated with chronic inflammation/immune responses upregulated in fibrotic lung:
Smooth muscle markers
Extracellular matrix (ECM) proteins
Pro-inflammatory cytokines, chemokines, and antioxidants
Immunoglobulins
IPF is a disease of persistent matrix deposition and remodeling. The high level of gene expression of both matrix-degrading proteins and proteins involved in matrix deposition suggests an active remodeling process.
In another study of patients diagnosed with UIP, high-resolution CT (HRCT) was performed as part of an effort to identify factors associated with UIP. Fifty-five percent of patients had mediastinal lymphadenopathy, suggesting the presence of an “antigen.”
Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with pathologic diagnosis of usual interstitial pneumonia. Chest. 2003;124:
Zuo F, Kaminski N, Eugui E, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci USA. 2002;99:
Zuo F, et al. Proc Natl Acad Sci USA. 2002;99: Hunninghake GW, et al. Chest. 2003;124:

15. Evolving Unified Hypothesis: Aberrant Response to Persistent Injury
Epithelial cells
Cell death – impaired reepithelialization
Basement
Membrane
Damage
Oxidative
Stress
Growth factors and other
products of epithelial
cell injury
Procoagulant
Activity
Myofibroblast
TH2-TH1
Balance
Cell survival –
resistance to apoptosis
Evolving Unified Hypothesis: Aberrant Response to Persistent Injury
As discussed on the previous slides, injury to the alveolar and capillary walls stimulates the release of molecules that damage the basement membrane. In the absence of an appropriate substrate, re-epithelialization cannot occur and, in an attempt to “wall off” the exposed area, chemokines and growth factors recruit fibroblasts and endothelial cells, which are stimulated to produce collagen and other matrix components. This can be accompanied by cell death and dysregulated repair of the epithelial/endothelial barrier. In the end, the formation of fibrotic regions of extracellular matrix proteins and myofibroblasts impedes the regeneration of the normal alveolar wall.
Multiple processes probably contribute to the pathogenic process. Defects or aberrant responses to hits at different stages may permit progression of the disease.
Vascular
Remodeling
Collagen – matrix remodeling
Courtesy of Paul W. Noble, MD, and Victor J. Thannickal, MD.

16. Increased angiogenesis
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
Fibrosis
Chemokine imbalance
Vascular Remodeling
Aberrant vascular remodeling has been found in conjunction with the fibrotic process in patients with IPF. This aberrant vascular remodeling supports fibrosis, and may contribute to increased shunt and hypoxemia. Increased angiogenic activity may be an important aspect of progressive fibrosis. This increased angiogenesis results from an imbalance between pro-angiogenic and anti-angiogenic chemokines. Vascular remodeling leads to anastomoses between the systemic/pulmonary microvasculature, increasing right-to-left shunt, contributing to hypoxemia.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25:
Strieter RM, Belperio JA, Keane MP. CXC chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S67-S69.
Increased angiogenesis
Aberrant
vascular
remodeling
Noble PW, Homer RJ. Clin Chest Med. 2004;25: , vii.
Strieter RM, et al. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-69.

17. Vascular Remodeling Is Regulated by Both Positive and Negative Factors
Basic fibroblast
growth factor (BFGF)
Vascular endothelial growth factor (VEGF)
Epidermal growth factor (EGF)
Endothelin
ELR (+) CXC chemokines
Angiostatin
Endostatin
Thrombospondin-1
Tissue inhibitors of metalloproteases
(TIMPs)
IFN-inducible ELR (-) CXC chemokines
Positive
Regulators
(Angiogenic)
Negative
Regulators
(Angiostatic)
Vascular Remodeling Is Regulated by Both Positive and Negative Factors
Vascular remodeling is regulated by the balance between positive (angiogenic) and negative (angiostatic) regulators. Angiogenic factors include basic fibroblast growth factor (BFGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), endothelin, and ELR+ CXR chemokines. Angiostatic factors include angiostatin, endostatin, thrombospondin-1, tissue inhibitors of metalloproteases (TIMPs), and IFN-inducible ELR- CXC chemokines.
Notably, treatment with the angiostatic ELR- CXC chemokine CXCL11 has been shown to reduce pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia, and extracellular matrix deposition in the lungs of bleomycin-treated mice, suggesting that targeting angiogenic pathways may be a potential therapeutic avenue for IPF, where an increase in lung angiogenesis has been observed.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25:
Burdick MD, Murray LA, Keane MP, et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med. 2005;171:
Strieter RM, Belperio JA, Keane MP. CXC chemokines in angiogenesis related to pulmonary fibrosis. Chest. 2002;122:298S-301S.
Courtesy of Robert M. Strieter, MD, FCCP.

18. 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
Clinical Progression of IPF
The traditional view of disease progression in patients with IPF is that there is a slow and linear decline in respiratory function that ultimately leads to respiratory failure and death. However, the emerging disease paradigm postulates that there is a step-wise progression of clinical disease. According to this theory, periods of relative stability may be interrupted by acute episodes of worsening lung function that may result in death.
Noble PW, et al. Idiopathic pulmonary fibrosis. Proceedings of the 1st Annual Pittsburgh International Lung Conference. October New insights into classification and pathogenesis usher in a new era of therapeutic approaches. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S27-S31.
King TE, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med. 2001;164:
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:
Noble PW. Am J Respir Cell Mol Biol. 2003;29:S27-S31.
King TE, et al. Am J Respir Crit Care Med. 2001;164:
Raghu G, et al. N Engl J Med. 2004;350:

19. 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
Clinical Progression of IPF (cont)
Several recent observations support this notion of a stepwise progression.
The risk of death is generally similar across various degrees of disease severity
Nearly half of the deaths in a recent large prospective randomized trial occurred prior to evidence of disease progression
Even patients with relatively stable lung function can experience sudden precipitous declines in lung function
Noble PW, et al. Idiopathic Pulmonary Fibrosis. New insights into classification and pathogenesis usher in a new era of therapeutic approaches. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S27-S31.
King TE, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med. 2001;164:
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:
Noble PW. Am J Respir Cell Mol Biol. 2003;29:S27-S31.
King TE, et al. Am J Respir Crit Care Med. 2001;164:
Raghu G, et al. N Engl J Med. 2004;350:

20. Progression of IPF: Acute Exacerbation vs Slow Decline
Step Theory of UIP/IPF Progression
Function/Symptoms
Respiratory
FVC
50%
Progression of IPF: Acute Exacerbation vs Slow Decline
An emerging theory suggests that IPF may involve multiple injuries to the lung over a period of time, and these injuries lead to acute exacerbations that result in periods of more rapid decline in lung function, and in some cases, respiratory failure and death. These acute exacerbations may occur following periods of relative stability.
Noble PW. Idiopathic pulmonary fibrosis. New insights into classification and pathogenesis usher in a new era of therapeutic approaches. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S27-S31. 1 2 3 4
Years
= events
= Acute exacerbation
Adapted from: Noble PW. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S27-S31.

21. Potential Strategies and Targets of Therapeutic Intervention
Promote repair/regeneration of the alveolar-capillary membrane
Inhibit fibroblast/myofibroblast activation or induce selective apoptosis
Prevent aberrant vascular and extracellular matrix remodeling and basement membrane damage
Limit oxidative stress responses
Augment innate immune responses
Potential Strategies and Targets of Therapeutic Intervention
Based on an increased understanding of the pathogenesis of IPF, several potential therapeutic strategies and targets of intervention have emerged. These include:
Promote repair/regeneration of the alveolar-capillary membrane
Inhibit fibroblast/myofibroblast activation or induce selective apoptosis
Prevent aberrant remodeling of the ECM, vascular remodeling and basement membrane damage
Limit oxidative stress responses
Augment innate immune responses (Restore TH1-TH2 balance)

22. 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
Take Home Messages
UIP is the histologic hallmark of IPF but there is substantial histopathologic variability with UIP often coexisting 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 of IPF is unpredictable: rapid declines related to acute exacerbations can occur following periods of relative stability