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Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy

Moisés Selman, MD; Talmadge E. King Jr., MD; and Annie Pardo, PhD
[+] Article and Author Information

From Instituto Nacional de Enfermedades Respiratorias and Universidad Nacional Autónoma de México, Mexico City, Mexico; and the University of California, San Francisco, San Francisco, California.


Acknowledgments: The authors thank Dr. Iasha Sznajder for providing the impetus for the writing of this manuscript.

Requests for Single Reprints: Moisés Selman, MD, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Mexico DF, Mexico; e-mail, mselman@conacyt.mx.

Current Author Addresses: Dr. Selman: Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Mexico DF, Mexico.

Dr. King: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, 1001 Potrero Avenue, Room 5H22, San Francisco, CA 94110.

Dr. Pardo: Facultad de Ciencias, UNAM, Apartado Postal 21-630, Coyoacan, Mexico DF 04000, Mexico.


Ann Intern Med. 2001;134(2):136-151. doi:10.7326/0003-4819-134-2-200101160-00015
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Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis. In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response. Clinical measurements of inflammation fail to correlate with stage or outcome, and potent anti-inflammatory therapy does not improve outcome. This review presents a growing body of evidence suggesting that idiopathic pulmonary fibrosis involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast–myofibroblast foci, which evolve to fibrosis. Progress in understanding the fibrogenic mechanisms in the lung is likely to yield more effective therapies.

Figures

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Figure 3.
Hypothetical scheme of the abnormal wound healing model for idiopathic pulmonary fibrosis.top leftbottom leftbottom righttop right

Multiple microinjuries damage and activate alveolar epithelial cells ( ), which in turn induce an antifibrinolytic environment in the alveolar spaces, enhancing wound clot formation. Alveolar epithelial cells secrete growth factors and induce migration and proliferation of fibroblasts and differentiation into myofibroblasts ( ). Subepithelial myofibroblasts and alveolar epithelial cells produce gelatinases that may increase basement membrane disruption and allow fibroblast–myofibroblast migration ( ). Angiogenic factors induce neovascularization. Both intra-alveolar and interstitial myofibroblasts secrete extracellular matrix proteins, mainly collagens. An imbalance between interstitial collagenases and tissue inhibitors of metalloproteinases provokes the progressive deposit of extracellular matrix ( ). Signals responsible for myofibroblast apoptosis seem to be absent or delayed in usual interstitial pneumonia, increasing cell survival. Myofibroblasts produce angiotensinogen that as angiotensin II provokes alveolar epithelial cell death, further impairing reepithelialization. FGF-2 = fibroblast growth factor-2; MMP = metalloproteinase; PAI-1, PAI-2 = plasminogen activator inhibitor-1, −2;PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β; TIMP = tissue inhibitors of metalloproteinases; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.

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