非诺贝特对DDC诱导小鼠原发性硬化性胆管炎的治疗作用与机制

Therapeutic Effect and Mechanism of Fenofibrate against DDC-induced Primary Sclerosing Cholangitis

目的:探讨非诺贝特对3,5-二乙氧基羰基-1,4-二氢-2,4,6-三甲基吡啶(DDC)诱导小鼠原发性硬化性胆管炎(PSC)的治疗作用与机制。方法:20只129/Sv小鼠随机分为正常组、模型组、治疗组、非诺贝特组,每组5只。正常组和非诺贝特组小鼠常规饮食,模型组和治疗组小鼠给予0.1%DDC饲料食饲,治疗组小鼠造模成功后给予非诺贝特25mg/kg剂量灌胃,2次/d进行治疗。HE染色观察肝组织病理改变,生物化学检测血清胆汁淤积和肝细胞损伤指标ALP、TBA、ALT、AST;qPCR检测肝组织胆汁酸合成、转运基因及炎症基因表达。结果:模型组小鼠造模成功时肝组织炎细胞浸润,胆汁淤积严重,胆管增生;血清生化、胆汁酸排泄基因、炎症基因转录水平明显升高(P<0.05或P<0.01);与模型组相比,非诺贝特给药后能逆转上述改变(P<0.05或P<0.01)。结论:非诺贝特对DDC诱导的小鼠PSC有良好的治疗作用,在非诺贝特干预下,DDC诱导的PSC小鼠胆汁酸代谢呈代偿性调控,炎症反应被明显抑制。

Objective:To study therapeutic effect and mechanism of fenofibrate against 3,5-diethoxycarbonyl-1, 4-dihydro-2,4,6-trimethylpyridine(DDC)-induced primary sclerosing cholangitis(PSC).Methods:Mice were fed a 0.1% DDC-supplemented diet to induce PSC for 5 days and given 25 mg/kg of fenofibrate by oral gavage twice a day for 8 days. HE staining was used to observe the pathological changes of liver tissue. ALT, AST, TBA and ALP were determined to detect hepatocyte injury and intrahepatic cholestasis. Q-PCR was used to measure bile acid synthesis and transport, inflammation gene expression in liver tissue.Results:In the Model group, infiltration, severe cholestasis, bile duct hyperplasia, bile acid excretion and inflammation gene expression were significantly increased(P<0.05 or P<0.01). Fenofibrate improved these changes in therapy group(P<0.05 or P<0.01). Conclusion:In DDC-induced mouse model, fenofibrate was effective for treatment of PSC. Under fenofibrate intervention, DDC-induced PSC mice adapted bile acid metabolism, and the inflammatory response was significantly inhibited pharmacologically.