CCAAT/enhancer-binding protein (C/EBP) homologous protein promotes alveolar epithelial cell senescence via the nuclear factor-kappa B pathway in pulmonary fibrosis.

Abstract

Alveolar epithelial cell senescence is a core event in the development of pulmonary fibrosis. Endoplasmic reticulum stress accelerates cellular senescence significantly; however, whether this stress promotes alveolar epithelial cell senescence in pulmonary fibrosis and its mechanisms are unclear. As a common intersection of endoplasmic reticulum stress signaling pathways, CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activates the oxidative stress pathway, which in turn accelerates cellular senescence. Therefore, we speculated CHOP pathway activation would affect endoplasmic reticulum stress-induced alveolar epithelial cell senescence in pulmonary fibrosis. In this study, we observed that alveolar epithelial cell senescence was accompanied by CHOP overexpression in idiopathic pulmonary fibrosis lung tissues. Bleomycin and tunicamycin combination models in vivo and in vitro showed that CHOP downregulation rescued alveolar epithelial cell senescence, reduced fibroblast activation mediated by the senescence-associated secretory phenotype, and improved pulmonary fibrosis pathology. Mechanistic studies showed that CHOP accelerated alveolar epithelial cell senescence by promoting reactive oxygen species generation, which activated the nuclear factor-kappa B pathway. Our study suggested that CHOP activates the downstream nuclear factor-kappa B pathway, thus contributing to endoplasmic reticulum stress-induced alveolar epithelial cell senescence and pulmonary fibrosis.