The protective effect of isoflurane pretreatment on liver IRI by suppressing noncanonical pyroptosis of liver macrophages

Abstract

BackgroundLiver ischaemia–reperfusion injury (IRI) is a major complication in the perioperative period and often leads to liver failure and even systemic inflammation. Sufficient evidence has demonstrated that isoflurane has anti-inflammatory effects. We aimed to determine whether isoflurane pretreatment protects against liver IRI and to investigate the mechanisms involved in this protection. MethodsMale C57BL/6 mice were pretreated with or without isoflurane and subjected to 90 min of 70% liver ischaemia, followed by reperfusion for 6 h. Liver tissues and serum were analysed to assess liver IRI. To probe the mechanisms, liver macrophages isolated from C57BL/6 mice were pretreated with or without emulsified isoflurane for 30 min before incubation with 1 µg/ml lipopolysaccharide (LPS) for 24 h. Inflammatory cytokine production, intracellular Ca2+ levels, caspase-11 expression, NF-κB transcription, and NLRP3 inflammasome activation were assessed by ELISA, an intracellular Ca2+ concentration assay, immunohistochemistry, or Western blotting. ResultsIsoflurane preconditioning significantly relieved liver IRI in mice and LPS-induced inflammation in liver macrophages. Additionally, isoflurane pretreatment inhibited caspase-11 expression and noncanonical pyroptosis-related production of cytokines (IL-1β and IL-18). Interestingly, isoflurane preconditioning reduced intracellular Ca2+ levels, NF-κB translocation, and NLRP3 inflammasome activation in LPS-induced macrophages. Our results indicated that isoflurane preconditioning ameliorated liver IRI by suppressing noncanonical pyroptosis in liver macrophages. These findings suggest that isoflurane could be a pharmacological agent for liver IRI prevention and thus deserves more attention and further investigation.