Involvement of α7nAChR in the hepatic-protective effect of remifentanil preconditioning in ischemia/reperfusion rats

Hepatic ischemia-reperfusion (I/R) injury is an unavoidable process in liver surgeries like transplantation and hepatectomy, and it greatly impairs postoperative liver function. Recent studies have shown that anesthetic agents, such as remifentanil, offer liver protection. However, the exact mechanisms of remifentanil's protective effects remain unclear. In this study, a rat hepatic I/R injury model and a hepatocyte BRL-3 A hypoxia/reoxygenation (H/R) model were successfully established, and remifentanil preconditioning (RPC) was administered. Liver function enzyme activities were measured using biochemical assays, and the extent of liver damage was assessed via HE staining as well as TUNEL staining. The survival rate and Apoptosis rate of BRL-3 A cells were determined by CCK-8 assay and flow cytometry, respectively. Levels of proinflammatory cytokines were quantified using ELISA. qRT-PCR and Western blotting analysis were employed to evaluate the expression of α7 nicotinic acetylcholine receptor (α7nAChR) and the phosphorylation of NF-κB. Loss-of- function experiments of α7nAChR were conducted to further elucidate the underlying molecular mechanism by which remifentanil protects the liver against I/R injury. The findings demonstrated that RPC markedly mitigated liver dysfunction, decreased hepatic cell necrosis and Apoptosis, and suppressed the inflammation in rats subjected to I/R. Furthermore, RPC provided protection for BRL-3 A cells against H/R-induced injury and inflammation. Notably, RPC upregulated α7nAChR expression in I/R liver tissue and H/R-exposed BRL-3 A cells while concurrently inhibiting NF-κB phosphorylation. However, the protective effects of RPC on hepatic I/R injury and H/R-induced BRL-3 A cells injury were abrogated by the administration of an α7nAChR antagonist or α7nAChR knockdown. Taken together, these data reveal a novel mechanism of remifentanil's hepatoprotective effect, which is that remifentanil alleviates hepatic I/R injury by upregulating α7nACh to inhibit inflammation mediated by NF-κB activation.

Hepatic ischemia-reperfusion injury; Inflammation; Nuclear factor-kappa b; Remifentanil; α7 nicotinic acetylcholine receptor.