对乙酰氨基酚诱导急性肝衰竭小鼠动物模型的建立

发布时间：2018-03-07 18:56

本文选题：对乙酰氨基酚　切入点：肝衰竭　出处：《肝脏》2016年05期 　论文类型：期刊论文

【摘要】：目的通过腹腔注射高剂量对乙酰氨基酚(APAP)构建稳定的用于研究药物导致急性肝衰竭的动物模型。方法本研究首先进行生存率实验,取60只C57BL/6小鼠随机分为4组,每组15只,分别腹腔注射0.9%氯化钠溶液及不同剂量(300 mg/kg、500 mg/kg、750 mg/kg)APAP后,观察不同组别72 h内小鼠的精神、活动状态和生存率。根据生存率分析结果,另选取180只C57BL/6小鼠,随机分为3组,分别腹腔注射0.9%氯化钠溶液、低剂量(300 mg/kg)和高剂量(750 mg/kg)APAP,每组分别在0、1、3、6、12 h等时间点随机选取12只小鼠,留取血清和肝组织,验证小鼠的生化和组织学是否符合急性肝衰竭的表现。结果生存率实验结果显示,0.9%氯化钠溶液组、300 mg/kg以及500 mg/kg组72 h内无小鼠死亡;750 mg/kg组72 h死亡率为100%,推测750 mg/kg组可能为急性肝衰竭导致的死亡。生化和组织学验证实验结果发现,对照组各时间点转氨酶均无明显升高;APAP处理的两组动物模型ALT3 h时开始升高,6 h时低剂量组ALT升高达到峰值[(6766.5±2001.27)IU/L],而高剂量组ALT于12 h达到(11707.58±1882.45)U/L(P0.01)。从HE病理染色来看,0.9%氯化钠溶液组各时间点肝脏形态结构正常。APAP处理的两组动物模型的肝组织学,主要表现为以中央静脉为中心的肝细胞变性坏死,并随时间延长,损伤范围逐渐扩大。低剂量组坏死周围界限清楚,汇管区肝细胞结构形态正常,12 h可见坏死区周围肝细胞增生表现。高剂量组表现为典型的急性大片状坏死特点,仅汇管区残存少量变性的肝细胞,细胞快速坏死后,留下空的网状纤维支架,肝窦淤积大量红细胞,未见肝细胞增生。HAI评分结果显示,高剂量组的HAI得分(7.33±1.5)显著高于低剂量组(5.25±2.26,P0.05)。结论 C57BL/6小鼠腹腔注射高剂量APAP(750 mg/kg)后,生化和组织学改变与急性肝衰竭相似,本研究构建的动物模型对于探索APAP导致的AHF的发病及进展机制研究具有潜在的应用价值。
[Abstract]:Objective to construct a stable animal model of acute hepatic failure induced by drugs by intraperitoneal injection of high dose paracetamol APAP.Methods in this study, 60 C57BL / 6 mice were randomly divided into 4 groups, 15 in each group. After intraperitoneal injection of 0.9% sodium chloride solution and different doses of 0.9% mg / kg sodium chloride for 750 mg/kg)APAP, the mental state, activity status and survival rate of different groups of mice within 72 hours were observed. According to the survival rate analysis, another 180 C57BL / 6 mice were randomly divided into 3 groups. Intraperitoneal injection of 0.9% sodium chloride solution, low dose of sodium chloride (300mg / kg) and high dose of 750mg / kg APP were performed in each group. 12 mice were randomly selected in each group at a time point of 12 hours, and serum and liver tissues were retained. Results the survival rate of 0. 9% sodium chloride solution group was 300 mg/kg and that of 500 mg/kg group within 72 h was 100. The mortality rate of 0. 9% sodium chloride solution group and #number0# mg/kg group within 72 h was estimated to be 100. The mg/kg group may have died of acute liver failure. Biochemical and histological studies showed that, There was no significant increase in aminotransferase at all time points in the control group. The two animal models treated with APAP showed no significant increase in ALT at the beginning of 6 h and reached the peak at 6 h in the low dose group [6766.5 卤2001.27 渭 mol / L], while the ALT in the high dose group reached 11707.58 卤1882.45U / L P0.01at 12 h. According to the pathological staining, 0.9% chlorine was found in the low dose group. Liver histology of two groups of animal models treated with APAP at different time points. The main manifestations were degeneration and necrosis of liver cells centered on central vein, and the range of damage gradually expanded with time. The limits of necrosis around necrosis were clear in low dose group. The proliferation of hepatocytes around the necrotic zone was observed in the high dose group after 12 h of normal morphology. In the high dose group, there were only a few degenerated hepatocytes in the catchment area, and only a small number of degenerated hepatocytes were found in the high dose group after rapid necrosis. The HAI score of high dose group (7.33 卤1.5) was significantly higher than that of low dose group (5.25 卤2.26 P0.05). Conclusion after C57BL / 6 mice were injected intraperitoneally with high dose of APAP(750 mg / kg, the HAI score of high dose C57BL / 6 mice was significantly higher than that of low dose group (7.33 卤1.5). The biochemical and histological changes are similar to those of acute liver failure. The animal model constructed in this study has potential application value in exploring the pathogenesis and progression of AHF induced by APAP.
【作者单位】：上海交通大学医学院附属仁济医院消化内科上海市消化疾病研究所;
【基金】：十二五科技重大专项(2012ZX09303-001,2012ZX09401004)
【分类号】：R575.3;R-332

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