Impaired GPX4 activity elicits ferroptosis in alveolar type II cells promoting PHMG-induced pulmonary fibrosis development

• Published in: Ecotoxicology and environmental safety Vol. 281; p. 116680
• Main Authors: Zhang, Wanjun, Sun, Zhaolong, Cheng, Wenting, Li, Xin, Zhang, Jianzhong, Li, Yanting, Tan, Haining, Ji, Xiaoya, Zhang, Lin, Tang, Jinglong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2024; Elsevier
• Subjects: Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - pathology; Animals; Cell Line; Cyclohexylamines - pharmacology; Ferroptosis; Ferroptosis - drug effects; GPX4 activity; Guanidines - pharmacology; Guanidines - toxicity; Lipid peroxidation; Lipid Peroxidation - drug effects; Male; Mice; Mice, Inbred C57BL; Phenylenediamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Polyhexamethylene guanidine; Pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - pathology; Quinoxalines; Spiro Compounds; Lipid peroxidation; Ferroptosis; Pulmonary fibrosis; Polyhexamethylene guanidine; GPX4 activity
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.116680

Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6 J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment. [Display omitted] •Ferroptosis of alveolar type II cells is involved in PHMG-induced pulmonary fibrosis.•Lipid peroxidation increase and GPX4 activity decrease play a central role in AT2 cell ferroptosis.•Ferroptosis inhibitors mitigate the occurrence of ferroptosis in PHMG-treated AT2 cells.