血红素加氧酶-1对急性肝衰竭大鼠肝组织HMGB1及炎症的影响-东南大学学报医学版

血红素加氧酶-1对急性肝衰竭大鼠肝组织HMGB1及炎症的影响

单位：1. 东南大学医学院, 江苏南京 210009;
2. 南京鼓楼医院普外科, 江苏南京 210008

分类号：R459.7

出版年·卷·期（页码）：2016·35·第二期（171-175）

摘要：

目的:探索血晶素(hemin)诱导血红素加氧酶-1(HO-1)过表达对急性肝衰竭(急性肝衰)大鼠肝脏中高迁移率族蛋白B1(HMGB1)及相关炎症因子的影响。方法:将96只SD大鼠按给药方法不同分成4组,即对照组、急性肝衰、hemin(HO-1诱导剂)组、锌原卟啉(znpp,HO-1抑制剂)组,每组24只。对照组腹腔注射生理盐水;急性肝衰组腹腔注射D-Gal 0.8 g·kg^-1及LPS 20μg·kg^-1制作肝衰竭模型;hemin、znpp组腹腔分别注射hemin 40μmol·kg^-1或znpp 50μmol·kg^-1,12 h后给予D-Gal和LPS,方法同急性肝衰组。检测各组大鼠诱导后24、72 h肝脏功能变化,比较4组大鼠肝脏组织病理学表现。应用RT-PCR及Western Blot检测肝组织中HO-1、HMGB1水平,ELISA检测TNF-α及IL-1β浓度;检测HO-1活性。结果:采用D-Gal和LPS成功建立了大鼠急性肝衰竭模型,与对照组比较,急性肝衰组谷氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、IL1β、TNF-α浓度及HMGB1水平均升高(P<0.05),肝脏组织损伤严重。与急性肝衰组比较:hemin组HO-1水平及活性上调,ALT、AST、IL1β、TNF-α浓度(P<0.05)及HMGB1水平显著降低,肝脏组织损伤缓解;而znpp组HO-1水平及活性降低, ALT、AST、IL1β、TNF-α浓度(P<0.05)及HMGB1水平升高,肝脏组织损伤加重。结论:在急性肝衰竭中HMGB1明显增加,HO-1的过表达可以缓解急性肝衰竭肝脏损伤,其机制与抑制HMGB1、IL1β、TNF-α的表达有关。

Objective:To investigate the effects of upregulation of heme oxygenase-1 with hemin on the expression of liver HMGB1 and associated inflammatory cytokines in rats during acute liver failure. Methods:Ninety six SD rats were divided into 4 groups(n=24) according to the processing conditions:control group, acute liver failure(ALF) group, hemin(HO-1 inducer) group, znpp(HO-1 inhibitor) group. Acute liver failure model was induced by intraperitoneally injection of D-Gal(0.8 g·kg^-1) and LPS(20μg·kg^-1), control group was given the same volume of saline. Hemin(40μmol·kg^-1 ) or znpp(50μmol·kg^-1) was given intraperitoneally starting from 12 hours before D-Gal and LPS administration. The level of ALT and AST were detected at 24, 72 h after injection and the liver histopathological sections were compared. RT-PCR and Western blot were used to calculate the mRNA and protein levels of HO-1 or HMGB1 in liver. Serum IL1β and TNF-α concentration were measured by ELISA. HO-1 activity was detected. ALF model were successfully induced. Results:ALF model were successfully induced by intraperitoneal injection of D-Gal and LPS. Compared with control group, the levels of ALT, AST, IL1β, TNF-α and HMGB1 in ALF group increased significantly(P<0.05), the structure of liver was damaged severely. Compared with ALF group, hemin treatment markedly increased the levels of HO-1 and HO-1 activity which inhibited the levels of ALT, AST, IL1β, TNF-α and HMGB1(P<0.05);While znpp treatment inhibited the levels of HO-1 and HO-1 activity thus leading to the up regulation of ALT, AST, IL1β、TNF-α and HMGB1(P<0.05) which aggravated liver damage. Conclusion:The level of HMGB1 is in accordance with the severity of ALF. HO-1 over-expression could ameliorate the damage of liver. Down-regulated HMGB1, IL1β and TNF-α might be its potential mechanism.

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