Remimazolam Reduces Sepsis-associated Acute Liver Injury By Activation Of Peripheral Benzodiazepine Receptors And P38 Inhibition Of Macrophages

Background and Objective:Sepsis has been defined as life-threatening organ dysfunction resulting from infection.Sepsis-Associated acute liver injury(SALI)is a common complication of sepsis,overactivation of early inflammatory response is the main cause of SALI.Sedation is an important therapeutic method in the clinical treatment of such patients.Conventional sedation drugs often cause the patients to have deep sedation and great influence on hemodynamics.Remimazolam is a novel type of benzodiazepine with a carboxylic acid ester bond,which has the characteristics of ultrafast sedative action and quick recovery of consciousness.It has been reported to have a potential advantage in sedative therapy in septic patients;however,its role and mechanism in the progression of SALI are unclear.In this study,aiming at the new benzodiazepine drug remimazolam,to explore its effect on liver inflammation in sepsis in addition to its sedative effect,and to preliminarily explore the mechanism of remimazolam on SALI through in vivo and in vitro experiments.It provides a new theoretical basis for the clinical prevention and treatment of sepsis acute liver injury.Methods:Lipopolysaccharide(LPS)plus galactosamine(D-GalN)treated rat model and LPS-challenged RAW264.7 cells model to construct inflammation model.The effect and molecular mechanism of remimazolam on SALI were studied in vitro and in vivo,and confirmed by peripheral benzodiazepine receptor inhibitor PK11195.Hepatic injury was assessed by quantifying transaminase levels,and examining liver pathology in the liver.Inflammatory responses were evaluated by determining levels of pro-inflammatory cytokines and chemokines in tissues and levels of p3 8 phosphorylation(p-p38)in the liver.Oxidative stress was evaluated by measuring total GSH,GSSG/GSH ratio,catalase and superoxide dismutase activity.Results:In vivo,SALIrat models showed significant liver damage as manifested by increased levels of transaminases,proinflammatory cytokines(TNF-α,IL-6,iNOS),chemokines(CCR2),and p-3 8;And the decrease of antioxidant(GSH)content and antioxidant enzyme(CAT,SOD)activity.Remimazolam treatment reduced liver injury and pathological changes suppressed pro-inflammatory reactions,and inhibit oxidative stress and p38 phosphorylation.The protective effect of remimazolam on liver injury was significantly blocked by PK11195.In LPS-stimulated RAW264.7 cells,it was found that treatment with remimazolam reduced the inflammatory response in LPS-treated cells in a time-dependent manner,attenuated oxidative stress and apoptosis,and decreased the level of p-p38.Conclusions:This study shows that Remimazolam can alleviate SALI by activating peripheral benzodiazepine receptors and inhibiting p38 phosphorylation,thus alleviating oxidative stress and inflammatory response in liver tissue.