LSC - 2017 - Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating, age-related lung disease with limited therapeutic options. Aging-related mechanisms such as cellular senescence have been proposed as a pathogenic driver. The lung epithelium that contains progenitor cells such as alveolar epithelial type II (ATII) cells represents a major site of tissue injury in IPF. Senescence of ATII cells is likely detrimental to lung repair and regeneration. ATII cell senescence and its potential effects in IPF, however, remain poorly understood. Here we analyzed epithelial cell senescence and its effects on pulmonary fibrosis. Gene set enrichment analysis revealed enrichment of senescence associated genes in ATII cells from experimental lung fibrosis. Fibrotic ATII cells exhibited increased senescence-associated ß-Galactosidase staining as analyzed by FACS. This was accompanied by enhanced gene expression of senescence-associated p16 and p21. Moreover, proteomic analysis of ATII supernatants showed secretion of factors associated with the senescence associated secretome (SASP). Importantly, human IPF lungs showed increased senescence-associated p16 gene and protein expression as compared to donors, an effect which was recapitulated in phATII cells. Pharmacological depletion of senescent cells with senolytic drugs from fibrotic 3D lung tissue cultures reduced fibrotic marker gene expression and increased the ATII cell marker surfactant protein C (Sftpc).In summary, fibrotic ATII cells exhibit increased senescence, which is accompanied by the secretion of SASP factors. Senolytic treatment increased ATII cell markers and decreased fibrotic gene expression, suggesting that senescence contributes to IPF pathogenesis.