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IPF Overview With a Focus on Pathophysiology and
Pathogenesis
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Objective
Discuss evolving concepts in the pathophysiology
and pathogenesis of IPF
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Evolving Classification of IPF
Interstitial Lung Diseases
UIP/IPF
Sarcoidosis Hypersensitivity Pneumonitis
DIP
RB-ILD
A heterogeneous group that included a number of
diseases
AIP
1970s
2002
NSIP
Cellular
Fibrotic
COP
Asbestosis LAM etc
LIP
Adapted from ATS/ERS Consensus Statement. Am J
Resp Crit Care Med. 2002165277-304.
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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 Consensus Statement. Am J Resp Crit Care
Med. 2002165277-304. ATS/ERS Consensus
Statement. Am J Resp Crit Care Med.
2000161646-664.
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Potential Risk Factors

• Familial (genetic)
• Smoking
• Environmental factors (eg, occupational exposure
  to wood dust or metal dust)
• Chronic aspiration associated with
  gastroesophageal reflux disease (GERD)
• Infectious agents

ATS/ERS Consensus Statement. Am J Resp Crit Care
Med. 2000161646-664.
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US Demographics

• Incidence gt 30,000 patients/year
• Prevalence gt 80,000 current patients
• Age of onset 40 to 70 years
• Two-thirds gt 60 years old at presentation
• Males gt females
• Caucasians gt minorities

ATS/ERS Consensus Statement. Am J Resp Crit Care
Med. 2000161646-664. Weycker D, et al.
Prevalence, Incidence, and Economic Costs of
Idiopathic Pulmonary Fibrosis. Paper presented
at CHEST 2002, November 2-7, 2002 San Diego,
California.
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Epidemiology of IPF
Prevalence
Incidence
120
300
100
250
Male
Male
Female
80
Female
200
60
150
40
100
20
50
0
0
45-54
55-64
65-74
75
45-54
55-64
65-74
75
Estimated 83,000 CurrentPatients in the United
States
Estimated 31,000 New Patients per Year in the
United States
Weycker D, et al. Prevalence, Incidence, and
Economic Costs of Idiopathic Pulmonary Fibrosis.
Paper presented at CHEST 2002, November 2-7,
2002 San Diego, California.
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Time (years)
Survival Curve for IIP Patients Grouped by
Histologic Classification
1.0
NSIP (n 30)
0.9
0.8
0.7
0.6
Discordant UIP (n 28)
0.5
Cumulative Proportion Surviving
0.4
0.3
Concordant UIP (n 51)
P lt0.0003
0.2
0.1
0.0
0 1 2 3
4 5 6 7
8 9
Flaherty KR, et al. Am J Respir Crit Care Med.
20011641722-1727.
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UIP A Histologic Study of Biopsy and Explant
Specimens

• Areas resembling NSIP often present in UIP
• If areas of NSIP and UIP are both present,
  UIPdetermines prognosis
• Potential confounding histologic features may be
  present in UIP
• Acute process superimposed on UIP
• Diffuse alveolar damage and BOOP superimposed
  on UIP
• Extensive honeycomb change may obscure
  diagnosis of UIP

Katzenstein AA, et al. Am J Surg Pathol.
200226(12)1567-1577.
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UIP Gene Chip Data

• Groups of genes significantly overexpressedin
  UIP
• Muscle markers
• Extracellular matrix, growth factors, and
  proteases
• Cytokines, chemokines, and antioxidants
• Complement, immunoglobulins, and amyloid

Zuo F, et al. Proc Natl Acad Sci USA.
200299(9)6292-6297.
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AgeGenetic factorsEnvironmental factorsNature
of injury
Histopathological Patterns of IIPs
LUNG INJURY

• Etiologic agent
• Recurrent vs single
• Endothelial vs epithelial

Histopathologic Pattern
DIP
RB-ILD
LIP
COP
NSIP
AIP
UIP
Inflammation
Fibrosis
Thannickal VJ, et al. Annu Rev Med.
200455395-417.
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What Is the Natural History of UIP/IPF?
Natural History/Pathogenesis of Disease
Beginning
Intermediate
End Stage
Stage/Phase
Slide courtesy of Robert Strieter, MD
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A Potential Natural History of the
Pathogenesis of NSIP ? UIP
NSIP
NSIP-F
Intermediate
Beginning
Stage/Phase
Flaherty KR, et al. Am J Respir Crit Care Med.
20011641722-1727. Slide courtesy of Robert
Strieter, MD
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Progression of IPFAcute Exacerbation vs Slow
Decline
Traditional View of UIP/IPF Progression
50
Respiratory Function/Symptoms
FVC
1
2
3
4
Years
FVC forced vital capacity
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Progression of IPFAcute Exacerbation vs Slow
Decline
Step Theory of UIP/IPF Progression
Respiratory Function/Symptoms
FVC
50
Acute exacerbation
1
2
3
4
0
Years
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Progression of Lung Fibrosis
Injury
Epithelial cells
Capillary
Slide courtesy of Paul Noble, MD
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Tissue Model of Lung Fibrosis
Cell death
Epithelial cells
Growth factors and other products of epithelial
cell Injury
Capillary
Myofibroblast
Collagen
Slide courtesy of Paul Noble, MD
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Pathology of IPF Peripheral Accentuation of
Disease
Slide courtesy of Kevin Leslie, MD
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Pathology of IPFTransition to Uninvolved Lung
Present in the Biopsy
Slide courtesy of Kevin Leslie, MD
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Pathology of UIP/IPF
Slide courtesy of Kevin Leslie, MD
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Fibroblastic Focus in UIP
Slide courtesy of Kevin Leslie, MD
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IPF Potential Contributing Pathways
GROWTH FACTOR
ANGIOSTATIC CHEMOKINES
DIRECT MARKERS OF FIBROSIS
IMMUNOMODULATING CYTOKINES AND CHEMOKINES
ANGIOGENIC FACTORS NEUTROPHIL CHEMOTAXIS/ACTIVATI
ON
ANTIMICROBIAL FACTORS
Slide courtesy of Robert Strieter, MD