激活PPARγ抑制异烟肼与利福平合用致大鼠肝损伤及HMGB1水平上调

Activation of PPARγ inhibits rat liver injury and HMGBl overexpression induced by isoniazid and rifampicin

目的探讨激活过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)对异烟肼与利福平合用致肝损伤的作用。方法以异烟肼和利福平合用制作大鼠肝损伤模型,以15d-PGJ2激活PPARγ。造模第14d和第28d分批处死大鼠,测定血清总胆红素(total bilirubin,TBIL)、直接胆红素(direct bilirubin,DBIL)、谷丙转氨酶(alanine aminotransferase,ALT),、谷草转氨酶(aspartate aminotransferase,AST)水平,观察大鼠肝病理学和超微结构变化,检测大鼠肝组织超氧化物歧化酶(superoxide dismutase,SOD)活性、丙二醛(malondialdehyde,MDA)含量,免疫组织化学测定肝高迁移率族蛋白B1(high mobility group box 1,HMGB1)表达。结果异烟肼和利福平合用所致肝损伤模型小鼠血清TBIL、DBIL明显升高,肝组织SOD活性显著降低,MDA含量升高,肝脂肪变性和炎症细胞浸润较明显,肝细胞线粒体及内质网结构破坏,HMGB1免疫反应性增强;PPARγ激动剂15d-PGJ2处理可明显抑制上述变化。结论 PPARγ激动剂15d-PGJ2可能通过抗氧化及抑制HMGB1表达对异烟肼、利福平合用致肝损伤发挥保护作用。

Objective To Study the effect of activation of peroxisome proliferator-activated receptorγ(PPARγ)on rat liver injury induced by isoniazid and rifampicin.Methods The model of rat liver injury was established by combined treatment of isoniazid and rifampicin.PPARγwas activated by15d-PGJ2.The rats were killed on14d and28d of model establishment,respectively.The serum levels of total bilirubin(TBIL),direct bilirubin(DBIL),alanine aminotransferase(ALT)and aspartate aminotransferase(AST)were measured.The pathological and ultrastructural changes of the liver tissue were observed.The activity of superoxide dismutase(SOD)and level of malondialdehyde(MDA)in the liver tissue were examined.The expression of high mobility group box1(HMGBl)was detected by Immunohistochemistry.Results In the models of rat liver injury induced by isoniazid and rifampicin,the serum TBIL and DBIL increased obviously,the hepatic SOD activity significantly decreased,and the hepatic MDA content increased.Hepatic steatosis and inflammatory cell infiltration were observed,as well as structural damage of the mitochondrium and endoplasmic reticulum in hepatocytes.HMGBl immunoreactivity increased.Activation of PPARγby15d-PGJ2obviously inhibited the changes above.Conclusion Activation of PPARγby15d-PGJ2can protect against the liver injury induced by isoniazid and rifampicin via antioxidation and inhibiting HMGB1expression.