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Update on Advances in the Pathophysiology and Pathogenesis of IPF

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Update on Advances in the Pathophysiology and Pathogenesis of IPF. Objective. Discuss the most recent developments in understanding the pathophysiology and pathogenesis of IPF. ATS/ERS Definition of Idiopathic Pulmonary Fibrosis.

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objective
Objective
  • Discuss the most recent developments in understanding the pathophysiology and pathogenesis of IPF
ats ers definition of idiopathic pulmonary fibrosis
ATS/ERS Definition of Idiopathic Pulmonary Fibrosis
  • A type of chronic fibrosing interstitial pneumonia
  • Unknown etiology limited to the lungs
  • Associated with a histologic pattern of usual interstitial pneumonia (UIP)

ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304.

slide4

300

250

Male

Female

200

150

100

50

0

45–54

55–64

65–74

75+

Epidemiology of IPF

Incidence

Prevalence

120

100

Male

Female

80

Per Hundred Thousand

Per Hundred Thousand

60

40

20

0

45–54

55–64

65–74

75+

Estimated 31,000 New Patients per Year in the United States

Estimated 83,000 CurrentPatients 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, CA.

elucidation of the natural history and pathogenesis of ipf
Elucidation of the Natural History and Pathogenesis of IPF
  • Allows investigation of potentially different mechanisms operative at early, intermediate, and end-stages
  • Facilitates implementation of targeted therapeutic intervention at specific stages of disease
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.

Nicholson AG. Thorax. 2004;59:500-505.

age genetic factors environmental factors nature of injury

Histopathological Patterns of IIPs

LUNG INJURY

AgeGenetic factorsEnvironmental factorsNature of 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. 2004;55:395-417.

slide8

Progression of IPF:Acute Exacerbation vs Slow Decline

Traditional View of UIP/IPF Progression

Respiratory

Function/Symptoms

50%

FVC

1

2

3

4

Years

FVC = forced vital capacity

slide9

Progression of IPF:Acute Exacerbation vs Slow Decline

Step Theory of UIP/IPF Progression

Respiratory

Function/Symptoms

FVC

50%

Acute exacerbation

=hits

1

2

3

4

0

Years

Am J Respir Cell Mol Biol. 2003;29(3 suppl):S1-S105.

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, active fibrosis, and end-stage honeycomb fibrosis
  • All areas of the lung are not involved

ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.

multiple hypotheses for the pathogenesis of ipf
Multiple Hypotheses for the Pathogenesis of IPF
  • Inflammation causes fibrosis
  • Noninflammatory (multiple hit) hypothesis: fibrosis results from epithelial injury and abnormal wound healing in the absence of chronic inflammation
  • Vascular remodeling: aberrant vascular remodeling supports fibrosis, and may contribute to increased shunt and hypoxemia

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25: 621-636, v.

Strieter R. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.

inflammatory hypothesis
Inflammatory Hypothesis
  • Inflammation causes fibrosis
    • Inflammatory concept was dominant in the 1970s and 1980s
      • IPF resulted from unremitting inflammatory response to injury culminating in progressive fibrosis
    • Role of inflammation remains controversial
      • Lack of efficacy of corticosteroids

Injury

Inflammation

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.

slide13

Progression of Lung Fibrosis

Injury

Epithelial cells

?

Endothelial

cells

Capillary

Slide courtesy of Paul Noble, MD.

slide14

Tissue Model of Lung Fibrosis

Cell death

Epithelial cells

Endothelial

cells

Growth factors and other

products of epithelial

cell Injury

Capillary

Myofibroblast

Collagen

Slide courtesy of Paul Noble, MD.

noninflammatory multiple hit hypothesis
Noninflammatory (multiple hit) Hypothesis
  • Fibrosis results from epithelial/endothelial injury and abnormal wound healing in the absence of chronic inflammation
    • Recurrent, unknown injury to distal pulmonary parenchyma causes repeated epithelial cell injury and apoptosis
    • Loss of alveolar epithelium exposes basement membrane to oxidative injury and degradation
    • Failure of re-epithelialization/re-endothelialization provides stimulus for persistent profibrotic growth factor production, persistent fibroblast proliferation, excessive deposition of ECM, and progressive 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.

Selman M, et al. Drugs. 2004;64:405-430.

noninflammatory multiple hit hypothesis16
Noninflammatory (multiple hit) Hypothesis

Recurrent pulmonary injury

Epithelial/

endothelial injury and apoptosis

TGF-b = transforming growth factor-beta

PDGF = platelet derived growth factor

IGF-1 = insulin-like growth factor-1

Loss of basement membrane

Failure of re-epithelialization/ re-endothelialization

Release of profibrotic growth factors (TGF-b, PDGF, IGF-1)

Fibroblast proliferation

ECM deposition

Progressive fibrosis with loss of lung architecture

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.

Selman M, et al. Drugs. 2004;64:405-430.

vascular remodeling hypothesis
Vascular Remodeling Hypothesis
  • 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

Increased angiogenesis

Aberrant

vascular

remodeling

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-S69.

defects in host defense mechanisms may contribute to fibrosis
Defects in Host Defense Mechanisms May Contribute to Fibrosis
  • Defects in endogenous host defense mechanisms (eg, IFN-g, PGE2 production) that limit fibrosis after acute lung injury may contribute to progressive fibrosis

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

potential therapeutic targets

Epithelial Restoration

Mitogens

Stem cell progenitors

Fibroproliferation

Aberrant Vascular Remodeling

Growth factors inhibitors

Angiostatic

molecules

Chemokine

antagonists

Potential Therapeutic Targets

Inflammation

Anti-oxidants

Cytokines

Host Defense

Interferon-gamma

Prostaglandin-E2

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.

Selman M, et al. Drugs. 2004; 64:405-430.

Burdick MD, et al. Am J Respir Crit Care Med. 2005;171:261-268.