PPARα激活可改善利福平合用异烟肼所致的大鼠肝损伤

Activation of peroxisome proliferator activated receptor alpha ameliorates Isoniazid and Rifampin induced liver injury in rats

目的观察过氧化物酶体增殖物激活受体α(PPARα)激动剂(WY14643)对利福平合用异烟肼所致肝损伤及其脂质过氧化、PPARαmRNA、胆盐输出泵(Bsep)mRNA和肿瘤坏死因子-α(TNF-α)mRNA表达的影响。方法48只SD雄性大鼠随机分为3组,每组16只。正常对照组:等量溶剂空腹灌胃处理;模型组:异烟肼+利福平各50 mg/(kg·d)空腹灌胃处理;WY14643干预组:异烟肼+利福平处理同模型组,同时腹腔内注射WY14643 1 mg/(kg·d)。正常对照组和模型组也同时腹腔内注射等量溶剂。于实验2周和4周分批处死大鼠,检测大鼠血清肝生化指标、肝组织超氧化物歧化酶(SOD)、丙二醛(MDA),观察其肝脏病理学改变,并采用RT-PCR法检测PPARα、Bsep、TNF-αmRNA的表达。结果 1与正常对照组比较,模型组血清总胆汁酸(TBA)、总胆红素(TBIL)、直接胆红素(DBIL)、碱性磷酸酶(ALP)升高,肝组织MDA升高,肝组织SOD减少(P<0.05);肝组织病理见肝细胞变性坏死及炎细胞浸润;肝PPARα、Bsep mRNA表达明显降低,TNF-αmRNA表达明显升高(P<0.01)。2与模型组比较,WY14643干预组肝组织SOD增加,MDA降低(P<0.05),肝脏病理学改善,肝PPARα、Bsep mRNA表达明显升高,TNF-αmRNA表达明显降低(P<0.01)。与2周模型组比较,WY14643干预组血清TBA、TBIL、DBIL降低(P<0.05),与4周模型组比较,WY14643干预组血清TBA降低(P<0.05)。结论 PPARα激活可通过抗氧化、调节PPARα、Bsep和TNF-αmRNA表达,改善利福平合用异烟肼所致的大鼠肝损伤。

Objective To observe the effects of peroxisome proliferator-activated receptor α （PPARα） agonist （WY14643） on Isoniazid and Rifampin induced liver injury in rats,and explore its influence on the lipid peroxidation and the expression of PPARα mRNA,bile salt export pump （Bsep）mRNA,tumor necrosis factor alpha（TNFα） mRNA.Methods 48 male SD rats were randomly divided into 3 groups,16 rats for each group.Normal control group was given equivalent solvent once daily.Model group was given intragastric administration of Isoniazid 50 mg/ （kg · d） ＋ Rifampin 50 mg/（kg · d）.WY14643 group was given Isoniazid 50 mg/（kg · d） ＋ Rifampin 50 mg/（kg · d） by intragastric administration and WY14643 1 mg/（kg · d） by intraperitoneal injection.The other two groups received daily intraperitoneal injection of the equivalent solvent.Every group was sacrificed respectively on day 14 and 28.The serum biochemical index of liver,the hepatic tissue superoxide dismutase（SOD）,malondialdehyde （MDA） were measured.The pathological changes in liver were observed.The expression of PPARα,Bsep,TNF-α mRNA was detected by RT-PCR.Results ① Compared with normal control group,serum total biliary acid （TBA）,total bilirubin（TBIL）,direct bilirubin（DBIL）,alkaline phosphatase（ALP） in model group were significantly elevated （P ＜ 0.05） ; SOD was significantly reduced （P ＜ 0.05）,MDA was significantly elevated （P ＜0.05） ; hepatocyte necrosis,fatty change,inflammatory cell infiltration in rat liver of model group were observed ; the expression of PPARα,Bsep mRNA was significantly reduced （P ＜ 0.01）,TNF-α mRNA expression was significantly elevated （P ＜ 0.01）.② Compared with model group,SOD was significandy elevated （P ＜ 0.05）.Hepatic tissue MDA was significantly reduced （P ＜0.05） in WY14643 group,the liver histological had improved.The expression of PPARo,Bsep mRNA was significantly elevated （P ＜ 0.01）,TNF-α mRNA expression was significantly reduced （P ＜ 0.01）.Compared with model group of week 2,serum TBA,TBIL,DBIL reduced in WY14643 group（P ＜0.05）.Compared with model group of week 4,serum TBA reduced in WY14643 group（P ＜ 0.05）.Conclusion Activation of PPARα ameliorated Isoniazid and Rifampin induced liver injury through antioxidanion and modulation of the expression of PPARα,Bsep and TNF-α mRNA.