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Impaired GPX4 activity elicits ferroptosis in alveolar type II cells promoting PHMG-induced pulmonary fibrosis
Wanjun Zhang1, Zhaolong Sun1, Wenting Cheng2
1Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, China; Departmental of Occupational and Environmental Health, School of Public Health, Qingdao University, Qingdao 266071, China.
Abstract:
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.
Insights
Polyhexamethylene guanidine (PHMG) inhalation causes pulmonary fibrosis by inducing ferroptosis, a cell death pathway. Inhibiting ferroptosis may offer a new treatment for this lung injury.
Area of Science:
- Toxicology
- Cell Biology
- Pulmonary Medicine
Background:
- Polyhexamethylene guanidine (PHMG) is a disinfectant linked to severe pulmonary fibrosis.
- Ferroptosis, an iron-dependent cell death, is implicated in chemical-induced lung injury.
Purpose of the Study:
- To investigate the role of ferroptosis in PHMG-induced pulmonary fibrosis.
- To explore PHMG's toxicity mechanism in lung cells and animal models.
Main Methods:
- Utilized C57BL/6J mice and MLE-12 alveolar cells for in vivo and in vitro studies.
- Assessed iron deposition, ferroptosis gene expression, antioxidant system, mitochondrial function, and lipid peroxidation.
- Evaluated the effects of ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1).
Main Results:
- PHMG exposure led to iron deposition and altered ferroptosis gene expression in mice.
- PHMG induced oxidative stress, mitochondrial damage, increased lipid peroxidation, and decreased GPX4 activity in MLE-12 cells.
- Ferrostatin-1 and Liproxstatin-1 treatments reversed these cellular changes.
Conclusions:
- Ferroptosis pathway plays a significant role in PHMG-induced pulmonary fibrosis.
- Targeting ferroptosis presents a potential therapeutic strategy for PHMG-related lung damage.
