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目的研究异烟肼、利福平合用致肝损伤时高迁移率族蛋白B1(HMGB1)与核因子-κB的关系及吡咯烷二硫代氨基甲酸盐(PDTC)对肝损伤的作用。方法 48只雄性SD大鼠随机分为3组:正常组、模型组(异烟肼+利福平,均50mg·kg-1·d-1)、PDTC组(异烟肼+利福平+PDTC,均50 mg·kg-1·d-1)。造模第14,28天,分批处死大鼠,检测大鼠血清胆汁酸(TBA)、总胆红素(TBIL)、直接胆红素(DBIL)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)水平,观察大鼠肝病理学变化,免疫组化法检测肝HMGB1蛋白表达,凝胶迁移实验测定核因子-κB活性。结果与正常组相比,模型组大鼠血清TBA、TBIL、DBIL、ALP明显升高(P<0.01),但ALT、AST差异无统计学意义;肝脂肪变性及炎症细胞浸润明显(P<0.01),肝内核因子-κB活性和HMGB1表达水平显著升高。与模型组相比,PDTC组血清TBA、TBIL、DBIL、ALP明显降低(P<0.01);肝病理学变化显著改善,肝内核因子-κB活性和HMGB1表达水平显著降低。结论抑制核因子-κB活性可下调HMGB1的表达;PDTC对异烟肼、利福平合用所致肝损伤的保护作用与其抑制NF-κB/HMGB1途径有关。
Objective To investigate the relationship between high mobility group box-1 (HMGB1) and nuclear factor-κB and the effect of pyrrolidine dithiocarbamate (PDTC) on hepatic injury induced by isoniazid and rifampin in combination with liver injury. Methods 48 male Sprague-Dawley rats were randomly divided into 3 groups: normal group, model group (isoniazid + rifampicin, 50 mg · kg -1 · d -1), PDTC group (isoniazid + rifampicin + PDTC, both 50 mg · kg-1 · d-1). The rats were sacrificed on the 14th and 28th day after the model was established. The serum levels of TBA, TBIL, DBIL, ALT, AST (aspartate aminotransferase AST) and alkaline phosphatase (ALP). The liver histopathological changes were observed. The expression of liver HMGB1 protein was detected by immunohistochemistry. Nuclear factor-κB activity was measured by gel migration assay. Results The levels of serum TBA, TBIL, DBIL and ALP in model group were significantly higher than those in normal group (P <0.01), but there was no significant difference in ALT and AST between the model group and the model group (P <0.01) ), Hepatic nuclear factor-κB activity and HMGB1 expression levels were significantly increased. Compared with model group, serum TBA, TBIL, DBIL and ALP in PDTC group were significantly decreased (P <0.01); hepatic pathological changes were significantly improved; hepatic nuclear factor-κB activity and HMGB1 expression were significantly decreased. Conclusion Inhibition of nuclear factor-κB activity can down-regulate the expression of HMGB1. The protective effect of PDTC on hepatic injury induced by isoniazid and rifampicin is related to the inhibition of NF-κB / HMGB1 pathway.