Cadmium exposure triggers alveolar epithelial cell pyroptosis by inducing mitochondrial oxidative stress and activating the cGAS-STING pathway.

Autor: Zhang CY; Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China.; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.; Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, 410078, Hunan, China., Ou AJ; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.; Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, 410078, Hunan, China., Jin L; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.; Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, 410078, Hunan, China., Yang NS; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.; Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, 410078, Hunan, China., Deng P; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.; Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, 410078, Hunan, China., Guan CX; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.; Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, 410078, Hunan, China., Huang XT; Xiangya Nursing School, Central South University, Changsha, 410013, Hunan, China., Duan JX; Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China. duanjiaxi91@csu.edu.cn.; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China. duanjiaxi91@csu.edu.cn., Zhou Y; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China. zhouyong421@csu.edu.cn.; Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, 410078, Hunan, China. zhouyong421@csu.edu.cn.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Nov 26; Vol. 22 (1), pp. 566. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1186/s12964-024-01946-7
Abstrakt: Background: Cadmium is a ubiquitous toxic metal and environmental pollutant. More and more studies have shown that cadmium exposure can damage lung function. Alveolar epithelial cells (AECs) are structural cells that maintain the stability of lung function. The injury of AECs is an essential determinant of many lung diseases. In the lung, cadmium accumulation can cause damage to AECs. However, the specific mechanism is still unclear. This study aimed to explore the key mechanism underlying the injury of AECs caused by cadmium exposure.
Methods: The main modes of death of AECs induced by cadmium exposure were evaluated in vivo and in vitro. Transcriptomic changes of AECs induced by cadmium exposure were analyzed using RNA-sequence. Mitochondrial ROS scavengers (mitoQ), voltage-dependent anion channel 1 (VDAC1) oligomer inhibitor (VBIT4), and cyclic GMP-AMP synthase (cGAS) inhibitor (RU.521) were used to assess whether cadmium exposure triggered pyroptosis of AECs by inducing mitochondrial stress to activate the cGAS-STING-NLRP3 axis.
Results: In this study, the expression of pyroptosis-related proteins was significantly up-regulated in the cadmium-exposed AECs, while the expression of apoptosis, necroptosis, and ferroptosis-related proteins had no significant up-regulated. The pan-caspase inhibitor ZVAD-FMK significantly reduced cell death. Thus, our research indicates that pyroptosis is the primary type of AEC death exported to cadmium. Mechanistically, RNA-seq and Western Blot results showed that cadmium exposure activated the cGAS-STING pathway in AECs and promoted pyroptosis by activating the NLRP3 inflammasome. Further investigation of the mechanism found that cadmium exposure caused mitochondrial oxidative stress, which led to mtDNA leakage into the cytoplasm and activated the cGAS-STING pathway. In addition, inhibition of the cGAS-STING pathway significantly alleviated lung injury induced by cadmium exposure in mice.
Conclusion: Our study confirmed that pyroptosis of AECs was a vital mechanism of lung injury after cadmium exposure in a cGAS-STING-dependent manner, which may provide a new target for the treatment of lung diseases induced by cadmium exposure.
Competing Interests: Declarations. Ethics approval and consent to participate: All animal protocols were approved by the Ethics Committee of the Basic Medical School of Central South University. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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