Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Division of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan; Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
Ecotoxicol Environ Saf. 2023 Nov 1;266:115555. doi: 10.1016/j.ecoenv.2023.115555. Epub 2023 Oct 12.
Mitochondrial dysfunction was reported to be involved in the development of lung diseases including chronic obstructive pulmonary disease (COPD). However, molecular regulation underlying metabolic disorders in the airway epithelia exposed to air pollution remains unclear. In the present study, lung bronchial epithelial BEAS-2B and alveolar epithelial A549 cells were treated with diesel exhaust particles (DEPs), the primary representative of ambient particle matter. This treatment elicited cell death accompanied by induction of lipid reactive oxygen species (ROS) production and ferroptosis. Lipidomics analyses revealed that DEPs increased glycerophospholipid contents. Accordingly, DEPs upregulated expression of the electron transport chain (ETC) complex and induced mitochondrial ROS production. Mechanistically, DEP exposure downregulated the Hippo transducer transcriptional co-activator with PDZ-binding motif (TAZ), which was further identified to be crucial for the ferroptosis-associated antioxidant system, including glutathione peroxidase 4 (GPX4), the glutamate-cysteine ligase catalytic subunit (GCLC), and glutathione-disulfide reductase (GSR). Moreover, immunohistochemistry confirmed downregulation of GPX4 and upregulation of lipid peroxidation in the bronchial epithelium of COPD patients and Sprague-Dawley rats exposed to air pollution. Finally, proteomics analyses confirmed alterations of ETC-related proteins in bronchoalveolar lavage from COPD patients compared to healthy subjects. Together, our study discovered that involvement of mitochondrial redox dysregulation plays a vital role in pulmonary epithelial cell destruction after exposure to air pollution.
线粒体功能障碍被报道与肺部疾病（包括慢性阻塞性肺疾病（COPD））的发展有关。然而，暴露于空气污染的气道上皮细胞代谢紊乱的分子调节仍不清楚。在本研究中，用柴油机排气颗粒（DEPs）处理肺支气管上皮 BEAS-2B 和肺泡上皮 A549 细胞，DEPs 是环境颗粒物的主要代表。这种处理引起细胞死亡，伴随着脂质活性氧（ROS）产生和铁死亡的诱导。脂质组学分析表明，DEPs 增加了甘油磷脂的含量。因此，DEPs 上调了电子传递链（ETC）复合物的表达，并诱导了线粒体 ROS 的产生。从机制上讲，DEP 暴露下调了 Hippo 转导转录共激活因子与 PDZ 结合基序（TAZ），TAZ 进一步被确定为铁死亡相关抗氧化系统的关键，包括谷胱甘肽过氧化物酶 4（GPX4）、谷氨酸-半胱氨酸连接酶催化亚基（GCLC）和谷胱甘肽二硫化物还原酶（GSR）。此外，免疫组织化学证实了 COPD 患者和暴露于空气污染的 Sprague-Dawley 大鼠支气管上皮中 GPX4 的下调和脂质过氧化的上调。最后，蛋白质组学分析证实了与 COPD 患者相比，健康受试者的支气管肺泡灌洗液中 ETC 相关蛋白发生了改变。总的来说，我们的研究发现，暴露于空气污染后，线粒体氧化还原失调的参与在肺上皮细胞破坏中起着至关重要的作用。
