Remimazolam inhibits apoptosis of endothelial and epithelial cells by activating the PI3K/AKT pathway in acute lung injury

作者：Ruohan Li, Chuchu Zhang, Jiajia Ren, Guorong Deng, Ya Gao, Xiao‐Ming Gao, Jiamei Li, Jingjing Zhang, Xi Xu, Xuting Jin, Xiaochuang Wang, Gang Wang · 发表于：International Immunopharmacology · 年份：2024 · DOI：10.1016/j.intimp.2024.113949 · 被引用次数：17 · 研究领域：Immune Response and Inflammation、Pharmacological Receptor Mechanisms and Effects、Respiratory Support and Mechanisms

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are significant burdens on global health. Remimazolam (REM), a novel sedative, has shown potential in its anti-inflammatory effects. However, a lack of evidence currently hinders our ability to determine if REM can improve ALI/ARDS. METHODS: We initially evaluated REM's impact on lung injury in a lipopolysaccharide (LPS)-induced ALI mouse model. Subsequently, a network pharmacology (NP) strategy and ribonucleic acid-sequencing (RNA-seq) technique were used to investigate the potential molecular mechanisms underlying REM's action against ALI. Finally, we carried out in vivo and in vitro experiments to validate our findings on these mechanisms. RESULTS: REM effectively mitigated lung injury in the mouse model. NP and RNA-seq analyses revealed significant enrichment of apoptosis-related pathways. Both in vivo and in vitro experiments revealed that REM significantly reduced levels of cleaved cysteine-aspartic acid-specific protease/proteinases 7 and 3 (cleaved Caspases-7 and -3) and cytochrome c (Cyt c) while enhancing the B-cell lymphoma 2 (Bcl-2)/Bcl-2-like protein 4 (Bax) ratio and phosphorylated protein kinase B (P-AKT) levels in lung tissue, endothelial cells, and epithelial cells. Furthermore, in vitro experiments confirmed that inhibiting the phosphoinositide 3-kinase (PI3K)/AKT pathway with LY294002 weakened REM's antiapoptotic effects. In addition, pretreatment with PK11195 (the ligand of ...