Sevoflurane Postconditioning Attenuates Hepatic Ischemia-Reperfusion Injury by Limiting HMGB1/TLR4/NF-κB Pathway via Modulating microRNA-142 in vivo and in vitro

Abstract

Preconditioning of sevoflurane (Sevo) has been demonstrated to protect the liver from ischemia/reperfusion (I/R) injury. However, it is unknown whether it has hepatoprotective when given at the onset of reperfusion (postconditioning), a protocol with more clinical impact. The present study aimed to explore the hepatoprotective effects of Sevo postconditioning against hepatic IR injury in vivo and in vitro and the possible mechanisms. Using a mouse model of hepatic I/R, Sevo postconditioning significantly improved hepatic injury after reperfusion, as demonstrated by reduced AST, ALT, and LDH serum levels and reduced histologic damage in liver tissues. Furthermore, Sevo postconditioning could suppress the apoptosis, inhibit oxidative stress and inflammatory response in liver tissue of HIRI mice, as well as improve the survival rate of HIRI mice. Through analyzing GSE72314 from the gene expression omnibus (GEO) database, it was demonstrated that microRNA (miR)-142 is downregulated by HIRI, which was reversed by Sevo treatment. Further investigation showed that agomiR-142 injection could enhance the hepatoprotective effects of Sevo postconditioning on I/R injury, while antagomiR-142 reversed these effects in mice. Notably, high mobility group box 1 (HMGB1), an important inflammatory factor, was directly targeted by miR-142 in hepatic cells, and we further found that Sevo could inhibit the expression of HMGB1 through up-regulating miR-142 expression in HIRI mice model. In addition, we found that I/R injury induced the activation of TLR4/NF-κB inflammatory pathway was partially suppressed by Sevo postconditioning, and miR-142 mediated the regulatory role of Sevo postconditioning. In line with the in vivo results, Sevo treatment improved the cell viability, inhibited cell apoptosis, oxidative stress and inflammatory response in vitro HIRI model, while these effects were reversed by antagomiR-142 transfection. Collectively, our findings demonstrated that Sevo postconditioning counteracts the downregulation of miR-142 provoked by I/R, in turn decreased the expression of HMGB1, blocking TLR4/NF-κB pathway activation, thus improving hepatic I/R injury. Our data suggest that Sevo may be a valuable alternative anaesthetic agent in liver transplantation and major liver surgeries.