复合因素致非酒精性脂肪性肝炎动物模型建立研究  

Establishment of Nonalcoholic Steatohepatitis Animal Model Caused by Multiple Factors

作　　者：谭婉莹 王淳[1,2] 周翠香 罗栋文 曾青山 李晓媛 杜仕静 扈晓宇 谭正怀[2] TAN Wanying;WANG Chun;ZHOU Cuixiang;UO Dongwen;ZENG Qingshan;LI Xiaoyuan;DU Shijing;HU Xiaoyu;TAN Zhenghuai(Chengdu University of Traditional Chinese Medicine,Chengdu 610000;Sichuan Provincial Key Laboratory of Quality and Innovation Research of Chinese Materia Medica,Sichuan Academy of Chinese Medicine Sciences,Chengdu 610041)

机构地区：[1]成都中医药大学,成都610000 [2]四川省中医药科学院四川省中药药理学重点学科,中药防治重大疾病药效学评价平台,中药材品质及创新中药研究四川省重点实验室,成都610041

出　　处：《中药药理与临床》2023年第3期82-87,共6页Pharmacology and Clinics of Chinese Materia Medica

基　　金：四川省中央引导地方发展专项(编号:2021ZYD0088);四川省科技厅项目(编号:2019JDPT0010)。

摘　　要：目的:非酒精性脂肪性肝炎(NASH)的发病率甚高,至今无有效防治药物上市。单一因素动物模型不利于阐述其发病机理及药物疗效评价。采用正交设计探讨四环素、地塞米松以及高脂乳剂的相互作用,以复制出具有多因素特点的NASH动物模型。方法:采用三因子两水平析因设计,以血液生化、肝脏脂质指标以及肝脏组织病理检查考察地塞米松40 mg/kg、四环素40 mg/kg、含丙基硫氧嘧啶和脱氧胆酸钠的高脂乳剂(硫氧胆酸乳)10 mL/kg在小鼠NASH形成过程中的交互作用,以建立的NASH最佳小鼠模型,进一步阐述其形成的内在机制。结果:地塞米松、硫氧胆酸乳单独使用,地塞米松与四环素联用,地塞米松与硫氧胆酸乳联用,四环素与硫氧胆酸乳联用,地塞米松、四环素及硫氧胆酸乳三者合用,均可产生NASH样改变。地塞米松40 mg/kg可引起小鼠肝脏功能受损,血清及肝脏中的TG含量升高,肝脏指数增加,肝组织NASH样改变明显,但血清以及肝脏TC含量无明显变化,体质量明显降低(P<0.05或P<0.01);硫氧胆酸乳可以引起小鼠血清ALT、AST活力及TC含量升高,肝脏TC含量明显升高,肝脏组织发生坏死及空泡样改变,其体质量降低,血清及肝脏TG含量均明显降低(P<0.05或P<0.01);地塞米松与硫氧胆酸乳联用时,其作用表现出明显的互补及相加的作用,主要表现为小鼠血清肝功能指标显著异常,血清及肝脏TC和TG含量均明显升高,肝脏湿质量、指数以及肝脏病理评分均明显升高(P<0.05或P<0.01)。结论:地塞米松与硫氧胆酸乳即可形成代表性比较强的NASH动物模型,提示NASH发病机制复杂,单纯从某一靶点出发难以对NASH的防治取得突破性进展;其次,临床上应根据患者肝功能的状态选择不同作用机理的降血脂药物,以避免药物性NASH的发生、发展。Objective:Nonalcoholic steatohepatitis(NASH)features high incidence and no available effective drugs on the market.Single-factor-induced animal model generally fails to reflect the pathogenesis and drug efficacy.Therefore,orthogonal design was used to study the interaction of tetracycline,dexamethasone,and high-fat emulsion and replicate the multi-factor-induced NASH model.Methods:Three-factor two-level factorial design was performed to investigate the interaction of 40 mg/kg dexamethasone,40 mg/kg tetracycline,and 10 mL/kg high-fat emulsion containing propylthiouracil and sodium deoxycholate(PSDHF)in the occurrence of NASH in mice based on blood biochemical indexes,liver lipid levels,and liver histopathology.On this basis,the optimal NASH mouse model was developed and the intrinsic mechanism was explored.Results:NASH-like changes were observed in mice in the cases of applying dexamethasone or PSDHF alone,both dexamethasone and tetracycline,both dexamethasone and PSDHF,both tetracycline and PSDHF,and dexamethasone in combination with tetracycline and PSDHF.Dexamethasone(40 mg/kg)caused liver injury,increase in TG level in serum and liver tissue and liver index,obvious NASH-like changes in liver tissue,no significant variation in TC level in serum and liver tissue,and significant reduction in body mass(P<0.05 or P<0.01).PSDHF induced increase in serum activities of ALT and AST,serum TC level,TC level in liver tissue,necrosis and vacuolation in the liver tissue,reduction in body mass,and significant decline in TG level in serum and liver tissue(P<0.05 or P<0.01).Dexamethasone and PSDHF showed obvious synergy,as manifested by the significant abnormality of liver indexes in serum,and significant increase in levels of TC and TG in serum and liver tissue,liver wet weight,liver index,and liver pathological score(P<0.05 or P<0.01).Conclusion:Dexamethasone and PSDHF can induce representative NASH in animal which shows the complex pathogenesis.It is difficult to make a breakthrough in the prevention and treatment of NASH f

关 键 词：非酒精性脂肪性肝炎 析因设计 地塞米松 四环素 高脂乳剂 

分 类 号：R575.1[医药卫生—消化系统] R-332[医药卫生—内科学]