Molecular Markers of Telomere Dysfunction and Senescence are Common Findings in the Usual Interstitial Pneumonia Pattern of Lung Fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive form of pulmonary fibrosis characterized pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (Non-IPF UIP) whose clinical course is similarly poor, suggesting common molecular drivers. Methods: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissue from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Results: Histopathologic changes in IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, noncaseating granulomas, airway centered inflammation or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs compared to age-similar, unused donor, controls. Telomere shortening was isolated to AECII cells when comparing telomere lengths between AECII and adjacent cells in individual patients. Molecular markers of senescence (p16, p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localized expression of these proteins to AECII cells. Conclusions: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the underlying clinical context.