Zhao Chen, Liang Fangte, Ye Mengling, Wu Siyi, Qin Yi, Zhao Lu, Zhang Lu, He Jing, Cen Liming, Lin Fei
Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China.
Guangxi Clinical Research Center for Anesthesiology, Nanning, China.
Cell Death Discov. 2023 Oct 4;9(1):368. doi: 10.1038/s41420-023-01663-z.
Lung ischemia/reperfusion injury (LIRI) is a complex pathophysiological process, with the histopathological hallmark of neutrophils migrating into the lungs. Neutrophil extracellular traps (NETs) have been suggested to exert a critical role in the pathogenesis of inflammation and infection in humans and animals, while the exact functions and underlying mechanisms of NETs in LIRI remain insufficiently elucidated. In this study, we investigated the role of pore-forming protein gasdermin D (GSDMD) on NETs release in LIRI induced by lung ischemia/reperfusion (I/R). We found that disulfiram, a GSDMD inhibitor, dramatically reduced NETs release and pathological injury in lung I/R in vivo and in vitro. Additionally, GSDMD caused mitochondrial DNA (mtDNA) leaking into the neutrophil cytosol, and then the cytoplasmic mtDNA activated the cGAS-STING signaling pathway and stimulated NETs formation in lung I/R. Furthermore, inhibition of cGAS/STING pathway could inhibit cytosol mtDNA mediated NETs formation.
肺缺血/再灌注损伤（LIRI）是一个复杂的病理生理过程，其组织病理学特征是中性粒细胞迁移至肺内。中性粒细胞胞外陷阱（NETs）在人和动物炎症及感染的发病机制中发挥关键作用，然而NETs在LIRI中的确切功能和潜在机制仍未得到充分阐明。在本研究中，我们探究了成孔蛋白gasdermin D（GSDMD）在肺缺血/再灌注（I/R）诱导的LIRI中对NETs释放的作用。我们发现，GSDMD抑制剂双硫仑在体内和体外均显著减少了肺I/R中NETs的释放及病理损伤。此外，GSDMD导致线粒体DNA（mtDNA）泄漏至中性粒细胞胞质溶胶中，随后胞质mtDNA激活cGAS-STING信号通路并刺激肺I/R中NETs的形成。此外，抑制cGAS/STING通路可抑制胞质溶胶mtDNA介导的NETs形成。
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