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

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 18-kDa translocator protein [TSPO]) attenuated REM's upregulation of the PI3K/AKT pathway and antiapoptotic effect in LPS-induced endothelial cells.

Conclusions: This study presents novel findings elucidating the beneficial effect of REM in ALI. This effect can be attributed to REM's ability to inhibit apoptosis by activating of the PI3K/AKT pathway in endothelial and epithelial cells. Additionally, REM targeted TSPO to regulate this pathway in endothelial cells. These results suggested a potential protective role for REM in ALI/ARDS management.