Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disea se characterized by fibroblast proliferation and extracellular matrix remod eling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailin g hypothesis holds that fibrosis is preceded and provoked by a chronic infl ammatory process that injures the lung and modulates lung fibrogenesis, lea ding to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether infl ammation is relevant to the development of the fibrotic process. Evidence s uggests 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 fibro sis. 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-infla mmatory therapy does not improve outcome. This review presents a growing bo dy of evidence suggesting that idiopathic pulmonary fibrosis involves abnor mal wound healing in response to multiple, microscopic sites of ongoing alv eolar epithelial injury and activation associated with the formation of pat chy fibroblast-myofibroblast foci, which evolve-to fibrosis. Progress in un derstanding the fibrogenic mechanisms in the lung is likely to yield more e ffective therapies.