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Hydrogen alleviates cell damage and acute lung injury in sepsis via PINK1/Parkin-mediated mitophagy

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Abstract

Background

Multiple organ failure (MOF) is the main cause of early death in septic shock. Lungs are among the organs that are affected in MOF, resulting in acute lung injury. Inflammation is an important factor that causes immune cell dysfunction in the pathogenesis of sepsis. Autophagy is involved in the process of inflammation and also occurs in response to cell and tissue injury in several diseases. We previously demonstrated that hydrogen alleviated the inflammation-induced cell injury and organ damage in septic mice.

Aim

The focus of the present study was to elucidate whether mitophagy mediates the inflammatory response or oxidative injury in sepsis in vitro and in vivo. Furthermore, we evaluated the role of mitophagy in the protective effects of hydrogen against cell injury or organ dysfunction in sepsis.

Method

RAW 264.7 macrophages induced by lipopolysaccharide (LPS) were used as an in vitro model for inflammation, and cecal ligation and puncture (CLP)-induced acute lung injury mice were used as an in vivo model for sepsis. The key protein associated with mitophagy, PTEN-induced putative kinase 1 (PINK1), was knocked down by PINK1 shRNA transfection in RAW 264.7 macrophages or mice.

Results

Hydrogen ameliorated cell injury and enhanced mitophagy in macrophages stimulated by LPS. PINK1 was required for the mitigation of the cell impairment in LPS-stimulated macrophages by hydrogen treatment. PINK1 knockdown abrogated the beneficial effects of hydrogen on mitophagy in LPS-stimulated macrophages. Hydrogen inhibited acute lung injury in CLP mice via activation of PINK1-mediated mitophagy.

Conclusion

These results suggest that PINK1-mediated mitophagy plays a key role in the protective effects of hydrogen against cell injury in LPS-induced inflammation and CLP-induced acute lung injury.

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Funding

This work was supported in part by National Natural Science Foundation of China (Nos. 81601667 to Hongguang Chen, 81671888 to Yonghao Yu, 81772043 to Xie Keliang, 81971879) Beijing, China; Natural Science Foundation of Tianjin (Nos. 18JCYBJC93700 to Hongguang Chen).

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Author notes

  1. Hongguang Chen, Huaying Lin, Beibei Dong and Yaoqi Wang have contributed equally.

Authors and Affiliations

  1. Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, 154 Anshan Road, Tianjin, 300052, People’s Republic of China

    Hongguang Chen, Huaying Lin, Beibei Dong, Yaoqi Wang, Yonghao Yu & Keliang Xie

  2. Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China

    Hongguang Chen, Huaying Lin, Beibei Dong, Yaoqi Wang, Yonghao Yu & Keliang Xie

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  1. Hongguang Chen
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Contributions

YY and KX designed the research and draft the manuscript; HC performed the animal research; BD cultures cell and collected sample in vitro; HL and YW carried out the detection of indicators. HL revised the manuscript after major revision. YY performed the results statistic. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yonghao Yu or Keliang Xie.

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The authors declare that they have no conflict of interest.

Human and animal rights

All experimental procedures were approved by the Institutional Animal Care and Use Committee of Tianjin Medical University and were performed in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals. All efforts were made to minimize animal suffering and the number of animals used.

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Chen, H., Lin, H., Dong, B. et al. Hydrogen alleviates cell damage and acute lung injury in sepsis via PINK1/Parkin-mediated mitophagy. Inflamm. Res. 70, 915–930 (2021). https://doi.org/10.1007/s00011-021-01481-y

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