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.

Cough in idiopathic pulmonary fibrosis

“…LESLIE [31] suggested that recurrent stretch injury caused by pressure changes during breathing may explain why fibrosis in IPF typically commences in the peripheral basal part of the lung. LESLIE [31] argues that in these areas the traction forces and alveolar collapse are greatest, leading to sheer stress, lung injury and activation of fibrotic cascades. By analogy, mechanical ventilation in IPF can be a risk factor for acute exacerbations of the pulmonary fibrosis [32].…”

“…1: traction leading to a weaker lower oesophageal sphincter tonus [45]; 2: microaspiration inducing epithelial damage [38,46]; 3: restriction inducing instability of the upper airway [39]; 4: intermitted hypoxaemia promoting profibrotic mechanisms [49]; 5: increased cough reflex sensitivity [22][23][24][25][26][27][28][29][30][31]; 6: pressure causing stretch injury and activation of fibrotic mechanisms [31]; 7: microaspiration causing an inflammatory reaction blocking the airway [53]; 8: obstruction increasing trans-diaphragmatic pressure [51,52]; 9: aspiration directly and acid reflux indirectly stimulate the cough reflex [6,47]; 10: cough increasing trans-diaphragmatic pressure [47]; 11: less central inhibition and inflammation increasing cough reflex sensitivity [54]. sensory nerves.…”

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

“…Pathologic fibrogenesis is poorly understood with respect to its initiating events and mechanisms that maintain ongoing fibrosis. Evidence suggests that type II alveolar epithelial cells experience injuries that initiate mesenchymal cell migration, proliferation, and activation of profibrotic pathways (4,5). The resulting fibrosis is likely the summation of complex interactions between alveolar epithelial cells, resident fibroblasts, circulating fibrocytes, and infiltrating inflammatory cells.…”

Effect of Pirfenidone on cough in patients with Idiopathic Pulmonary Fibrosis

“…LESLIE et al [13] proposed that recurrent stretch injury, caused by pressure changes during breathing, promotes fibrosis. Cough might be an additional source of mechanical stress, and could theoretically contribute to a pro-fibrotic feedback loop.…”