Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts

作者：Ruijuan Guan, Yuan Liang, Jingpei Li, Jian Wang, Ziying Li, Zhou Cai, Hua Guo, Yaowei Fang, Ran Lin, Wei Qing Liu, Lan Wang, Qiuyu Zheng, Jingyi Xu, You Zhou, Jing Qian, Mingjing Ding, Jieping Luo, Yuanyuan Li, Kai Yang, Dejun Sun, Hongwei Yao, Jianxing He, Wenju Lu · 发表于：European Respiratory Journal · 年份：2022 · DOI：10.1183/13993003.02307-2021 · 被引用次数：169 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Neonatal Respiratory Health Research、Cystic Fibrosis Research Advances

Background Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development; however, the role of BMP4 in modulating lung fibrosis remains unknown. Methods The aim of this study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts and lung samples from patients with IPF. Results BMP4 expression was downregulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with transforming growth factor (TGF)-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. BMP4 overexpression using adeno-associated virus 9 vectors showed preventative and therapeutic efficacy against lung fibrosis. In vitro , BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Pink1 silencing by short-hairpin RNA trans...