敲除趋化因子受体3对延缓原发性胆汁性肝硬化模型病情进展的作用  

The role of CXCR3 knockout in alleviating the primary biliary cirrhosis in mice

作　　者：费允云[1] 张文[1] 高金明[2] 刘斌[3] 张奉春[1] 

机构地区：[1]中国医学科学院北京协和医院风湿免疫科,100032 [2]中国医学科学院北京协和医院呼吸科,100032 [3]青岛大学医学院附属医院风湿免疫科

出　　处：《中华风湿病学杂志》2011年第3期147-150,217,共5页Chinese Journal of Rheumatology

基　　金：基金项目：国家自然科学基金（30470767）;国家“十一五”科技支撑计划（2008BAl59803）

摘　　要：目的建立原发性胆汁性肝硬化（PBC）动物模型，研究趋化因子受体3（CXCR3）及其配体干扰素诱导蛋白10（CXCLIO）在PBC发病中的作用。方法6~8周雌性C57BL／6J小鼠72只，分为3组：C57BL／6J野生鼠PBC模型组、正常对照组、CXCR3基因敲除（CXCR34-）c57BL／6J小鼠PBC模型组，PBC模型组小鼠每次腹腔注射5mg／kg的聚肌苷酸（聚）胞苷酸（P01y I：C），每周2次，共24周，第8、16、24周处死小鼠，收集小鼠肝脏、血清标本；酶联免疫吸附试验（ELISA）检测血清抗线粒体抗体（AMA）和CXCLIO滴度；病理分析肝脏炎性细胞浸润程度。计量资料两样本问比较选用t检验。结果第8、16、24周对照组血清中AMA—M，的平均吸光度（4）值分别为0．17＋0．04、0．19±0．07、0．20±0．06；PBC野生鼠模型的AMA—M，的平均4值分别为0．70＋0．41、O．48±0．35、0．69±0．44；CXCR3-／-小鼠模型的平均A值分别为0．56±0．25、0．46±0．35、0．85±0．34。第8、16、24周PBC野生鼠模型组碱性磷酸酶（ALP）平均值分别为（115±33）、（119±32）、（133±52）U／ml；PBCCXCR3＋鼠模型组ALP平均值分别为（106±29）、（112±29）、（122±60）U／ml；对照组小鼠ALP平均值分别为（65＋7）、（70±9）、（77＋10）U／ml。与对照组相比，PBC模型组的AMA滴度和ALP水平明显增高（P〈0．05）；CXCR3刮、鼠和野生鼠PBC模型组之间的AMA滴度和ALP水平差异无统计学意义。PBC模型组小鼠第8周可见小胆管周围单个核细胞浸润，胆管上皮细胞变性坏死，基底膜不完整；第16周可见小叶间胆管增生，炎性细胞浸润；第24周可见小胆管损伤、闭塞，胆管内胆栓形成，周围炎性细胞浸润，肉芽肿形成，炎症从门静脉区发展到肝实质。CXCR34-鼠PBC模型组病变程度较同期的野生鼠PBC模型组轻，第8周可见部分小胆管周围少量炎性细胞浸润，第16周汇管区炎性�Objective To generate an antoimmune cholangitis animal model and investigate whether CXCR3 and its ligand were involved in the pathogenesis of primary biliary cirrhosis （PBC）. Methods Female C57BL/6 wild-type （WT） mice and CXCR3 knockout （CXCR3^-） mice were injected with 5 mg/kg of poly I： C intra-peritoneally twice a week for 24 consecutive weeks. Liver specimens were collected to evaluate the degree of cell infiltration. AMA was assayed by ELISA. Differences in pathology were compared between CXCR3^- mice and wild-type. Student＇s test was used to assess the differences. Results Anti-mitochon-drial antibody （AMA） and alkaline phosphatase （ALP） level were elevated significantly in the sera of all poly I：C injected mice compared with control mice. AMA titers in serum were increased in the poly I：C injected WT mice compared with that of the control mice at week 8, 16, and 24 respectively （0.70±0.41 vs 0.17±0.04, 0.48±0.35 vs 0.19±0.07, 0.69±0.44 vs 0.20±0.06, P〈0.01 ）. There was no significant difference between AMA titers in the serum of WT PBC mice and CXCR34- PBC mice （0.70±0.41 vs 0.56±0.25, 0.48±0.35 vs 0.46± 0.35, 0.69±0.44 vs 0.85±0.34）. Serum alkaline phosphatase （ALP） levels were raised among the poly I：C injected WT mice compared with WT controls （115±33） vs （65±7） U/ml; （119±32） vs （70±9） U/roll （133± 52） vs （77±10） U/nd. The serum ALP levels in CXCR3- PBC mice were （]06±29）, （l12±29）and （122± 60） U/ml at week 8, 16 and 24 respectively. There was no significant difference in ALP level between WT and CXCR3- mice PBC model. Considerable numbers of infiltrating cells were detected at the portal areas 8 weeks after poly I：C. injection, which progressed up to 24 weeks. At week 24, the interlobular bile ducts were lost and bile-plug were evident. Compared to WT mice model, this results revealed that CXCR3 4- mice, had fewer loci of inflammation and significant reduction in total inflammatory cells in their li

关 键 词：肝硬化 胆汁性 受体 趋化因子 干扰素诱导蛋白10 CXCR3基因敲除小鼠 

分 类 号：R575.2[医药卫生—消化系统]