抑制Drp1改善线粒体动力学失衡并缓解脓毒症诱导的急性肺损伤

Abstract

Background Acute lung injury (ALI) is a major complication of sepsis. Sepsis-induced ALI (S-ALI) is closely related to excessive mitochondrial fission induced by the fission protein dynamin-related protein 1 (Drp1), and this process may be modulated in part through the calcineurin (CaN)/Drp1 signaling pathway. This work aimed to assess the protective impact of Mdivi-1, a Drp1 inhibitor, on ALI caused by sepsis and to clarify the associated molecular mechanisms. Methods In vivo experiments employed the cecal ligation and puncture (CLP) method to induce sepsis-associated ALI in mice. In vitro, an MLE-12 mouse alveolar epithelial cell model was induced by lipopolysaccharide (LPS). Lung injury and inflammation were evaluated through histological staining, lung wet-to-dry ratio, and measurement of inflammatory cytokines; Western blot was used to assess proteins related to mitochondrial dynamics, the CaN/Drp1 signaling pathway, and apoptosis; cell apoptosis was analyzed using fluorescence-based assays, and reactive oxygen species (ROS) accumulation as well as mitochondrial membrane potential (ΔΨm) changes were measured. Results CLP-induced mice and LPS-treated MLE-12 cells exhibited significant lung injury, elevated inflammatory cytokines, decreased mitochondrial fusion proteins, increased fission proteins, elevated ROS levels, reduced ΔΨm, decreased ATP production, and increased apoptosis. Mdivi-1 treatment markedly alleviated CLP/LPS-induced lung injury and inflammation, restored the expression of Occludin and zonula occludens-1 (ZO-1), improved abnormal mitochondrial dynamics, reduced ROS levels, restored ΔΨm and adenosine triphosphate (ATP) content, and inhibited apoptosis. In addition, Mdivi-1 blocked dysregulated activation of the CaN/Drp1 signaling pathway. Conclusion The Drp1 inhibitor Mdivi-1 alleviates S-ALI by inhibiting the CaN/Drp1 signaling pathway, improving mitochondrial dynamics imbalance, reducing oxidative stress and apoptosis, and partially restoring