4-羟基苯并噁唑-2-酮对四氯化碳诱导大鼠肝纤维化的改善作用及机制研究

Study on Improvement Effect and Mechanism of 4-hydroxy-2-benzoxazolone on Carbon Tetrachloride-induced Hepatic Fibrosis in Rats

目的:观察4-羟基苯并噁唑-2-酮(HBOA)对四氯化碳(CCl4)诱导大鼠肝纤维化的改善作用及其机制。方法:将雄性SD大鼠随机分为正常对照组、模型组、秋水仙碱组(阳性对照,0.4 mg/kg)和HBOA低、中、高剂量组(50、75、100 mg/kg),每组12只。除正常对照组大鼠灌胃等体积生理盐水外,其余各组大鼠均灌胃50%CCl4-橄榄油溶液(2 mL/kg,首剂量加倍),每周2次,连续12周,复制肝纤维化模型。自造模第9周起,各给药组大鼠均灌胃相应药物,正常对照组和模型组大鼠均灌胃等体积0.6%羧甲基纤维素钠溶液,每天1次,连续4周。末次给药后,检测各组大鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、白细胞介素1β(IL-1β)、IL-10的含量以及肝组织中核因子κB p65(NF-κB p65)、肿瘤坏死因子α(TNF-α)、IL-6、细胞间黏附因子1(ICAM-1)蛋白的表达水平。结果:与正常对照组比较,模型组大鼠肝组织中NF-κB p65阳性表达明显增多,且其血清ALT、AST、IL-1β含量以及肝组织中NF-κB p65、TNF-α、IL-6、ICAM-1蛋白表达水平均显著升高,血清IL-10含量显著降低(P<0.05)。与模型组比较,各给药组大鼠肝组织中NF-κB p65阳性表达均有不同程度的减弱,且其血清ALT、AST、IL-1β含量以及肝组织中NF-κB p65、TNF-α、IL-6、ICAM-1蛋白表达水平均显著降低,血清IL-10含量均显著升高(P<0.05)。结论:HBOA对CCl4致大鼠肝纤维化具有一定的改善作用,其作用机制可能与其阻断NF-κB信号通路继而减轻炎症反应以及下调ICAM-1蛋白的表达有关。

OBJECTIVE:To observe the improvement effect and mechanism of 4-hydroxy-2-benzoxazolone(HBOA)on carbon tetrachloride-induced hepatic fibrosis in rats.METHODS:Male SD rats were randomly divided into normal control group,model group,colchicine group(positive control,0.4 mg/kg)and HBOA low-dose,medium-dose and high-dose groups(50,75,100 mg/kg),with 12 rats in each group.Except for normal control group was given constant volume of normal saline intragastrically,other groups were given 50%CCl4-olive oil solution(2 mL/kg,initial dose double)intragastrically,twice a week,for consecutive 12 weeks,to induce hepatic fibrosis model.Since the 9th week of modeling,administration groups were given relevant medicine intragastrically.Normal control group and model group were given constant volume of 0.6%Carboxymethylcellulose sodium solution intragastrically,once a day,for consecutive 4 weeks.After last administration,the serum contents of ALT,AST,IL-1βand IL-10,the protein expression of NF-κB p65,TNF-α,IL-6 and ICAM-1 in liver tissue were determined.RESULTS:Compared with normal control group,the positive expression of NF-κB p65 in liver tissue was increased significantly in model group;serum contents of ALT,AST and IL-1βas well as protein expression of NF-κB p65,TNF-α,IL-6 and ICAM-1 in liver tissure were increased significantly,while serum content of IL-10 was decreased significantly(P<0.05).Compared with model group,the positive expression of NF-κB p65 in liver tissue were decreased to different extents in administration groups;serum contents of ALT,AST and IL-1βas well as protein expression of NF-κB p65,TNF-α,IL-6 and ICAM-1 in liver tissue were decreased significantly,while serum content of IL-10 was increased significantly(P<0.05).CONCLUSIONS:HBOA can improve carbon tetrachloride-induced hepatic fibrosis in rats,and the mechanism of which may be associated with relieving inflammatory reaction by blocking NF-κB signaling pathway and down-regulating the protein expression of ICAM-1.