首页|右美托咪定调控p62/Keap1/Nrf2信号轴对LPS诱导大鼠肝脏损伤的保护机制研究

右美托咪定调控p62/Keap1/Nrf2信号轴对LPS诱导大鼠肝脏损伤的保护机制研究

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目的 探究右美托咪定(Dexmedetomidine,Dex)调控自噬受体蛋白p62/Kelch样ECH 相关蛋白-1(Kelch-like ECH-associated protein1,Keap1)/核因子 E2 相关因子 2(Nuclear factor E2 related factor 2,Nrf2(p62/Keap1/Nrf2)通路对脂多糖(Lipopolysaccharide,LPS)诱导大鼠肝脏损伤的保护作用机制.方法 选取SD大鼠50只,随机将大鼠分为5组,分别为空白对照组(Sham组)、LPS诱导肝脏损伤模型组(LPS组)、LPS诱导+Dex干预组(Dex组)、Keap1/Nrf2信号轴抑制剂组(KI696组)、LPS诱导+Dex干预+KI696组(Dex+KI696组).统计各组大鼠干预后血清、肝功能因子,包括总胆固醇(Total cholesterol,TC)、总血脂(Total glyceride,TG)、丙氨酸氨基转移酶(Alanine transaminase,ALT)、天门 冬氨酸氨基转移酶(Aspartate aminotrans-ferase,AST),肝组织炎症因子白细胞介素-6(Interleukin-6,IL-6)、白细胞介素-8(Interleukin-8,IL-8)、白细胞介素-1β(Interleukin-1β,IL-1β)、肿瘤坏死因子-α(Tumor necrosis factor-α,TNF-α),氧化应激指标丙二醛(Malondialdehyde,MDA)、超氧化物歧化酶(Superoxide dismutase,SOD)、谷胱甘肽(Glutathione,GSH)、过氧化氢酶(Catalase,CAT)水平差异.HE染色分析各组大鼠肝脏组织病理形 态;Western-blot检测各组 大鼠肝脏组织p62/Keap1/Nrf2信号轴关键蛋白p62、Keap1、Nrf2,铁死亡关键蛋白前列腺素内过氧化物合酶(Prostaglandin endoperoxide synthase,PTGS2)、谷胱甘肽过氧化物酶 4(Glutathione peroxidase 4,GPX4)、铁蛋白基因(Recombinant hu-man ferritin heavy chain,FTH1)表达.结果 与 Sham 组相比,LPS 组 p62、TC、TG、ALT、AST、IL-6、IL-8、IL-1 β、TNF-α、MDA、PTGS2 表达升高,Keap1、Nrf2、SOD、GSH、CAT、GPx4、FTH1 表达降低(P＜0.05).与 LPS 组相比,Dex 组 p62、TC、TG、ALT、AST、IL-6、IL-8、IL1β、TNF-α、MDA、PTGS2 表达降低,Keap1、Nrf2、SOD、GSH、CAT、GPx4、FTH1 表达升高(P＜0.05);KI696 组 Keap1、PTGS2、SOD、GSH、CAT、GPx4、FTH1 表达降低,Nrf2、TC、TG、ALT、AST、IL-6、IL-8、IL-1β、TNF-α、MDA 表达升高(P＜0.05).与 KI696 组相比,Dex+KI696 组Keap1、PTGS2、SOD、GSH、CAT、GPx4、FTH1 表达升高(P＜0.05).结论 右美托咪定通过抑制p62活性,激活Keap1/Nrf2通路活性发挥抗氧化应激损伤、抗炎症反应作用,减缓铁死亡程度,达到保护肝组织的作用.
Pretreatment mechanism of dexmedetomidine regulating the p62/Keap1/Nrf2 signaling axis against lipopolysaccharide(LPS)induced liver injury in rats
Objective To explore the protective mechanism of dexmedetomidine(Dex)on lipopolysaccha-ride(LPS)induced liver injury in rats by regulating the p62/Keap1/Nrf2 signaling axis.Methods 50 SD rats were selected for inclusion in the study and randomly divided into 5 groups:blank control group(Sham group),LPS induced liver injury model group(LPS group),LPS induced+Dex intervention group(Dex group),Keap1/Nrf2 signal axis inhibitor group(KI696 group)and LPS induced+Dex intervention+KI696 group(Dex+KI696 group).The levels of serum lipid,liver function factor total cholesterol(TC),total glyceride(TG),alanine transaminase(ALT),aspartate aminotransferase(AST),Interleu-kin-6(IL-6),Interleukin-8(IL-8),Interleukin-1β(IL-1β),tumor necrosis factor-α,malondialdehyde(MDA),superoxide dismutase(SOD),glutathione(GSH)and catalase(CAT)were statistically different in each group after intervention.HE staining was used to analyze the pathological morphology of liver tis-sue in each group of the rats;Western blot was used to detect the expression levels of p62/Keap1/Nrf2 signaling axis key proteins(p62,Keap1,Nrf2)and iron death key proteins(PTGS2,GPx4,FTH1)in the liver tissues of the rats in each group.Results Compared with Sham group,LPS group showed increased expression of p62,TC,TG,ALT,AST,IL-6,IL-8,IL-1β,TNF-α,MDA and PTGS2,while the ex-pression of Keap1,Nrf2,SOD,GSH,CAT,GPx4 and FTH1 was decreased(P＜0.05);Compared with LPS group,Dex group showed a decrease in the expression of p62,TC,TG,ALT,AST,IL-6,IL-8,IL-1 β,TNF-α,MDA and PTGS2,while the expression of Keap1,Nrf2,SOD,GSH,CAT,GPx4 and FTH1 was increased(P＜0.05).The KI696 group showed a decrease in the expression of Keap1,PTGS2,SOD,GSH,CAT,GPx4andFTH1,while the expression of Nrf2,TC,TG,ALT,AST,IL-6,IL-8,IL-1 β,TNF-α and MDA was increased(P＜0.05);Compared with KI696 group,Dex+KI696 group showed increased expression of Keap1,PTGS2,SOD,GSH,CAT,GPx4 and FTH1(P＜0.05).Conclusion Dexmetomidine exerts antioxidant stress damage and anti-inflammatory response in LPS in-duced liver injury in rats by inhibiting p62 activity and activating Keap1/Nrf2 pathway activity,slowing down ferroptosis and achieving liver tissue protection.

lipopolysaccharide(LPS)liver injurydexmetomidineP62/Keap1/Nrf2 signal axisferroptosis

孙沈阳、陈烨、钮中辉

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南通市海门区人民医院麻醉科,江苏 南通 226100

脂多糖 肝损伤 右美托咪定 p62/Keap1/Nrf2信号轴 铁死亡

江苏省卫健委卫生财务研究项目

YSHL0824-220

2024

10.3969/j.issn.1009-5551.2024.07.007

新疆医科大学学报
新疆医科大学

新疆医科大学学报

CSTPCD
影响因子：0.76
ISSN：1009-5551
年,卷(期)：2024.47(7)