Sevoflurane suppresses NLRP3 inflammasome-mediated pyroptotic cell death to attenuate lipopolysaccharide-induced acute lung injury through inducing GSK-3? phosphorylation and activation

Pyroptosis is a type of programmed cell death, and pyroptosis-associated inflammatory response is closely associated with the pathogenesis of acute lung injury (ALI). Sevoflurane, a common clinical anesthetic, has been reported as therapeutic drug for ALI. However, the detailed mechanisms by which sevoflurane ameliorates ALI have not been fully delineated. In this study, we found that sevoflurane phosphorylated and activated the GSK-3 beta to suppress LPS-induced pyroptotic cell death, inflammation and ALI. Specifically, in the LPS-induced ALI mice models, sevoflurane attenuated lung damages and fibrosis, and restrained the production of the proinflammatory cytokines. Also, LPS increased the expression levels of pyroptosis-related proteins to promote pyroptotic cell death in ALI mice lung tissues, and LPS-induced pyroptotic cell death was reduced by sevoflurane co-treatment. Moreover, the potential underlying mechanisms were uncovered, and we illustrated that sevoflurane promoted GSK-3 beta activation in LPS-treated ALI mice lung tissues, and re-activation of GSK-3 beta by the PI3K/Akt pathway inhibitor LY294002 suppressed LPS-induced pyroptotic cell death in vivo. Consistently, in the in vitro macrophages, our data hinted that LPS-induced pyroptotic cell death were also reversed by sevoflurane. Collectively, the above results suggest that sevoflurane re-activated GSK-3 beta to suppress LPS-induced pyroptotic cell death, inflammation and ALI.