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.
Highlights
Hepatic ischemia/reperfusion injury (HIRI) is a pathophysiological condition post major liver surgeries or transplantation, which results in severe liver damage
Liver damage induced by I/R was visualized using hematoxylin and eosin (HE) staining and was graded using the Suzuki score, and the results indicated severe liver damage such as necrosis and inflammatory cell infiltration in HIRI group; Sevo postconditioning significantly attenuated liver damage compared with HIRI group (Figures 1D,E), which suggest that Sevo postconditioning could partially protect against hepatic I/R injury
Since the I/R-induced hepatic injury is partly due to induction of hepatocyte apoptosis (Quesnelle et al, 2015), the expression level of cleaved caspase 3 was measured by IHC and the results showed that the levels of cleaved caspase 3 expression in HIRI group were significantly increased compared with Sham group, while Sevo postconditioning attenuated the levels of caspase 3 induced by I/R (Figures 1F,G)
Summary
Hepatic ischemia/reperfusion injury (HIRI) is a pathophysiological condition post major liver surgeries or transplantation, which results in severe liver damage. Ischemic preconditioning (sevoflurane are administered upon the occurrence of ischemia) is one of the methods used to attenuate IR injury (Theodoraki et al, 2016). Ischemic postconditioning was considered as a novel approach to minimize IR injury, which is defined as repeated brief cycles of ischemia and reperfusion after the prolonged period of ischemia and before the sustained reperfusion (de Rougemont et al, 2009; Santos et al, 2010). This technique is operative and easy to perform in patients undergoing liver surgeries or transplantation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
