Idiopathic Pulmonary Fibrosis May Be a Disease of Recurrent, Tractional Injury to the Periphery of the Aging Lung: A Unifying Hypothesis Regarding Etiology and Pathogenesis

Abstract

Context.—Idiopathic pulmonary fibrosis is a progressive, fatal lung disease occurring in older individuals. Despite 50 years of accrued data about the disease, little progress has been made in slowing functional loss or in decreasing patient mortality. Objective.—To present a novel hypothesis on the etiology and pathogenesis of idiopathic pulmonary fibrosis. Design.—Published data are reviewed regarding the epidemiology, clinical presentation, natural history, radiologic findings, and pathologic findings in patients with idiopathic pulmonary fibrosis. Results.—Patients with idiopathic pulmonary fibrosis may be predisposed genetically to tractional injury to the peripheral lung. The result is recurrent damage to the epithelial-mesenchymal interface, preferentially at the outer edges of the basilar lung lobules where tractional stress is high during inspiration, compliance is relatively low, and there is a greater tendency for alveolar collapse at end-expiration. A distinctive “reticular network of injury” (the fibroblast focus) forms, attended by a prolonged phase of wound repair (tear and slow repair). Discrete areas of alveolar collapse are observed in scar at the periphery of the lung lobules. The cycle repeats over many years resulting in progressive fibrous remodeling and replacement of the alveoli in a lobule by bronchiolar cysts surrounded by scar (honeycomb lung). Abnormalities in surfactant function are proposed as a potential mechanism of initial lung damage. Age of onset may be a function of a required threshold of environmental exposures (eg, cigarette smoking) or other comorbid injury to the aging lung. Conclusions.—Evidence supporting this hypothesis is presented and potential mechanisms are discussed. A potential role for contributing cofactors is presented.