右美托咪定对脂多糖诱导小鼠肝损伤的保护作用及机制

Protective effect and mechanism of dexmedetomidine on lipopolysaccharide-induced liver injury in mice

目的探究右美托咪定(DEX)对脂多糖(LPS)诱导肝损伤模型小鼠肝功能的保护机制研究。方法选择36只6~8周龄健康雄性C57BL/6J小鼠,随机分为3组,模型组和DEX处理组均采用LPS诱导肝损伤模型,DEX处理组在诱导前注射30μg/kg DEX,对照组不做处理。药物作用6 h后麻醉采血并取出肝脏,检测白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)等血清炎性因子和谷丙转氨酶(GPT)、谷草转氨酶(GOT)、总胆红素(TBIL)等肝功能指标,观测丙二醛(MDA)、活性氧(ROS)、超氧化物歧化酶(SOD)、谷胱甘肽(GSH)等肝组织氧化应激水平,采用Western blot检测肝组织中糖原合成酶激酶/丝裂原活化蛋白激酶磷酸酶/核相关因子2(GSK-3β/MKP-l/Nrf2)通路蛋白表达。结果DEX能降低因LPS诱导的肝损伤引起的GPT、GOT、TBIL、MDA、ROS、IL-1β、TNF-α、IL-6、GSK-3β指标水平的升高(P<0.05);DEX能提高因LPS诱导的肝损伤引起的SOD、GSH、MKP-l、Nrf2指标水平的降低(P<0.05)。结论右美托咪定对脂多糖诱导肝损伤模型小鼠肝功能具有保护作用,可能是通过调节GSK-3β/MKP-l/Nrf2通路影响氧化应激反应和炎症反应而发挥作用的。

Objective To explore the protective mechanism of dexmedetomidine(DEX)on liver function in mice with lipopolysaccharide(LPS)-induced liver injury.MethodsThirty-six healthy male C57 mice aged 6-8 weeks were randomly divided into three groups(model group,DEX group and control group).The model group and DEX group were treatedwith LPS-induced liver injury,the DEX treated group was injected with 30μg/kg DEX before induction,while the control group was not treated.After 6 hours of drug delivery,the blood was collected under anesthetization and the liver was removed.The levels of liver function indexes(GPT,GOT,TBIL),oxidative stress indexes(MDA,ROS,SOD,GSH),and serum inflammatory factors(IL-1β,TNF-α,IL-6)were measured.Western blotting method was performed to detect the expression of glycogen synthase kinase/mitogen-activated protein kinase phosphatase 1/nuclear factor erythroid 2-related factor 2(GSK-3β/MKP-1/Nrf2)pathway protein in liver tissue.ResultsDEX can reduce the increase of GPT,GOT and TBIL levels in the liver injury induced by LPS(P<0.05);reduce the increase of MDA and ROS levels(P<0.05),while increase the decrease of SOD and GSH levels induced by the liver injury(P<0.05);suppress the increase of IL-1β,TNF-αand IL-6 levels induced by the liver injury(P<0.05).DEX also inhibits GSK-3β,promote MKP-1 and Nrf2 expression(P<0.05)in liver injury.ConclusionDexmedetomidine showed protective effect on liver function in LPS-induced liver injurymodel,and it may be achieved by inhibiting GSK-3β/MKP-1/Nrf2 related oxidative stress and inflammatory responses.