[Selectively activating melanocortin 4 receptor acts against rat sepsis-induced acute liver injury via HMGB1/TLR4/NF-κB signaling pathway].

Objective To observe the effect of selective activation of melanocortin 4 receptor (MC4R) on the rats with sepsis-induced acute liver injury. Methods Sixty-four male SD rats were randomly grouped into sham operation group (PBS treatment after sham operation), cecal ligation and puncture (CLP) group (sepsis model was established by CLP), Ro27-3225 treatment group (Ro27-3225 treatment after CLP), and Ro27-3225 sham operation control group (Ro27-3225 treatment after sham operation), 16 rats for each group (ten rats were used to observe general condition and 72-hour survival after operation. Then, six rats were used to collect blood and liver samples). These groups were intraperitoneally injected with PBS or Ro27-3225 (180 μg/kg) 30 minutes after operation. Heart rate (HR), mean arterial pressure (MAP), aspartate transaminase (AST) and alanine transaminase (ALT) were measured 24 hours after operation. After execution of the rats, pathological changes of liver tissues were observed by HE staining. The levels of Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1) and caspase-3 mRNA in liver tissues were analyzed by reverse transcription PCR. The expression of nuclear factor-κB (NF-κB) p65 in hepatocytes was detected by immunohistochemical staining, which was followed by analysis of nuclear positive rate of NF-κB p65. Results Compared with the sham operation group, CLP group showed decreased 72-hour survival and MAP, significantly increased levels of AST and ALT, hepatic cords disorder, hepatocyte swelling, and diffuse inflammatory cell infiltration; the levels of TLR4, HMGB1 and caspase-3 mRNA in liver tissues remarkably increased, and the positive rate of NF-κB p65 in hepatocytes went up as well. However, compared with the CLP group, the Ro27-3225 treatment group was found with obviously increased 72-hour survival and MAP, inhibited levels of AST and ALT, attenuated damage of liver tissues, decreased levels of TLR4, HMGB1 and caspase-3 mRNA in liver tissues, and significantly downregulated positive rate of NF-κB p65 in hepatocytes. Conclusion Sepsis causes liver injury. Selectively activating MC4R can reduce sepsis-induced acute liver injury in rats, which may act via inhibiting HMGB1/TLR4/NF-κB signaling pathway to relieve inflammation response.

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