Diesel exhaust PM2.5 greatly deteriorates fibrosis process in pre-existing pulmonary fibrosis via ferroptosis

作者：Dayong Yue, Qian Zhang, Jinjin Zhang, Weili Liu, Libang Chen, Meirong Wang, Rongrong Li, Qin Song, Xiaodong Song, Yunxia Ji · 发表于：Environment International · 年份：2022 · DOI：10.1016/j.envint.2022.107706 · 被引用次数：141 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Air Quality and Health Impacts、Ferroptosis and cancer prognosis

Fine particulate matter (PM2.5) has been widely reported to contribute to the pathogenesis of pulmonary diseases. The direct hazardous effect of PM2.5 on the respiratory system at high concentrations in vitro and in vivo have been well identified. However, its effect on the pre-existing respiratory diseases of patients at environment-related concentrations remains unclear. Diesel exhaust PM2.5 as a primary representative of ambient PM2.5 fine particles were used to investigated the effect of PM2.5 on the fibrosis progression of existing pulmonary fibrosis disease models. This study reported that PM2.5 could result in the enhanced sensitivity to fibrotic response, which may be ascribed to ferroptosis induced by PM2.5 in damaged lung areas. Proteomic analysis revealed that the upregulation of HO-1 as a key mechanism in the ferroptosis and exacerbation of pulmonary fibrosis induced by PM2.5. As a result, HO-1 degraded heme-containing protein and released iron in fibrotic cells, leading to generation of mitochondrial ROS and impaired mitochondrial function. Transmission electron microscopic assay verified that PM2.5 entered the mitochondria of fibrotic cells and was accompanied by significant mitochondrial morphological changes characterized by increased mitochondrial membrane density and reduced mitochondrial size. The HO-1 inhibitor zinc protoporphyrin and mitochondrion-targeted antioxidant Mito-TEMPO significantly attenuated PM2.5-induced ferroptosis and exacerbation of fibros...