转录因子AP-1抑制剂T5224减轻模型小鼠胆汁淤积性肝损伤  

Transcription factor AP-1 inhibitor T5524 alleviates cholestatic liver injury in mouse models

作　　者：李胜涛 卢卓恒 罗佳 闫征 汤治元[1] LI Sheng-tao;LU Zhuo-heng;LUO Jia;YAN Zheng;TANG Zhi-yuan(Department of Physiology and Pharmachology,School of Medicine,Ningbo University,Ningbo 315211,China)

机构地区：[1]宁波大学医学院生理药理学系,浙江宁波315211

出　　处：《基础医学与临床》2022年第11期1721-1726,共6页Basic and Clinical Medicine

基　　金：浙江省基础公益技术研究计划(LGD19H070001,LY20H030001);宁波市社会公益研究计划(202002N3160)。

摘　　要：目的探究转录因子激活蛋白1(AP-1)在胆汁淤积性肝损伤中的作用与机制。方法将ICR小鼠随机分为对照组、胆汁淤积性肝损伤模型组和AP-1抑制剂T-5244干预模型组,每组5只。α-萘异硫氰酸盐(ANIT)和T-5224分别溶于玉米油,各组小鼠实验前过夜禁食12 h,正常对照组给予玉米油灌胃;胆汁淤积性肝损伤模型组和T-5224组均同步给予120 mg/kg的单剂量ANIT灌胃处理;T-5224组于ANIT灌胃前0.5~1 h按100 mg/kg腹腔注射选择性AP-1抑制剂T-5224,并于24 h后给予第2个剂量。所有小鼠给予ANIT 48 h后收集血清,处死小鼠并采集肝脏、胆囊等标本,通过生物化学、组织病理学、分子生物学等方法比较各组小鼠之间的肝损伤和炎性反应。结果与对照组相比,胆汁淤积性肝损伤模型组的肝损伤指标谷草转氨酶(AST)和谷丙转氨酶(ALT)分别从(7.2±1.6)μmol/L、(2.5±0.5)μmol/L上升至(132.0±48.4)μmol/L、(94.2±22.2)μmol/L,提示肝损伤严重,造模成功。与模型组相比,T-5224干预组中AST、ALT则分别显著减少至(48.4±12.8)μmol/L与(23.1±2.6)μmol/L;蛋白质水平上,T-5224干预组AP-1通路被抑制,CXCL10、CCL2等趋化因子的表达分别被抑制90%、79%,肝损伤显著减少。结论AP-1介导的炎性反应在ANIT诱导的小鼠胆汁淤积性肝损伤中发挥重要作用。Objective To explore the effect and underlying mechanism of transcription factor activator protein-1(AP-1)in cholestatic liver injury.Methods ICR mice were randomly divided into control group,cholestatic liver injury model group and AP-1 inhibitor(T-5244)intervention model group(5 in each group).α-naphthyl isothiocyanate(ANIT)and T-5224 were dissolved in corn oil respectively.The mice were fasted for 12 h overnight before the experiment.The control group was treated with corn oil by oral gavage.The cholestatic liver injury model group and the T-5244 intervention model group were treated with ANIT 120 mg/kg(a single dose).The T-5244 intervention group was intraperitoneally injected with T-5224 inhibitor AP-1100 mg/kg 0.5~1 h before ANIT treatment.The T-5224 treatment was repeated 24 h later.After 48 hrs,all mice were sacrificed to collect serum,liver and gallbladder.The biochemical markers,histopathological changes and liver injury among different groups were analyzedand compared.Results Compared with the control group,the biomarker of liver injury,aspartate alanine aminotransferase(ALT),and aminotransferase(AST),increased from(7.2±1.6)μmol/L and(2.5±0.5)μmol/L to(132.0±48.4)μmol/L and(94.2±22.2)μmol/L in cholestatic liver injury group.It confirmed a successful development of cholestatic model.In contrast with the cholestatic liver injury group,the two biomarkers in the T-5224 intervention group were reduced to(48.4±12.8)μmol/L and(23.1±2.6)μmol/L respectively.At the protein level,activation of AP-1 was inhibited.Expression of CXCL10,CCL2 were inhibited by 90%and 79%respectively in the T-5224 intervention group,and liver injury was significantly reversed.Conclusions AP-1 mediated chemotaxis plays an important role in ANIT-induced cholestatic liver injury.

关 键 词：激活蛋白1(AP-1) 胆汁淤积 肝损伤 趋化反应 

分 类 号：R366[医药卫生—病理学]