牛磺熊去氧胆酸联合柳氮磺胺吡啶对小鼠结肠炎模型的药效作用及机制  

Effects and mechanisms of tauroursodeoxycholic acid combined with sulfasalazine against colitis model of mice

作　　者：贾立伟[1] 李欣[2] 朱文娅[2] 孙涛[1,2] 

机构地区：[1]第二军医大学海军临床医学院,北京100048 [2]海军总医院消化内科,北京100048

出　　处：《解放军医学院学报》2015年第11期1134-1137,1145,共5页Academic Journal of Chinese PLA Medical School

基　　金：首都医学发展科研基金项目(2009-3083)~~

摘　　要：目的观察牛磺熊去氧胆酸(tauroursodeoxycholic acid,TUDCA)联合柳氮磺胺吡啶(sulfasalazine,SASP)对小鼠实验性结肠炎的药效作用,初步探讨牛磺熊去氧胆酸干预结肠炎模型的可能机制。方法 5%葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导小鼠实验性结肠炎模型。药物组给予SASP(500 mg/kg)、TUDCA(100 mg/kg)、TUDCA+SASP灌胃;正常组及模型组给予0.9%氯化钠注射液。1次/d,共8 d。观察小鼠一般状态、疾病活动指数(disease activity index,DAI)、结肠长度改变及病理组织学积分;采用免疫组化SP法检测结肠组织Hes1、Atoh1、Cdx2的表达情况,ELISA法检测血清中TNF-α、IL-6的表达量。结果正常组、TUDCA组、SASP组、TUDCA/SASP联合组的DAI分别为0.10±0.23、2.37±0.46、2.17±0.55、1.94±0.34,其组织学损伤评分分别为0.00±0.00、6.60±1.71、6.10±1.45、4.5±1.27,均低于模型组(3.43±0.47和9.40±1.26),差异均有统计学意义(P<0.01);TNF-α、IL-6蛋白表达水平,正常组(46.12±8.35)ng/L、(26.89±5.45)ng/L,TUDCA组(56.48±9.02)ng/L、(27.60±4.76)ng/L,SASP组(59.15±11.09)ng/L、(26.42±5.08)ng/L,均低于模型组[(70.64±7.93)ng/L、(35.12±3.51)ng/L],差异均有统计学意义(P<0.05);正常组、TUDCA组Hes1蛋白表达分别为0.26±0.12、0.40±0.10,低于模型组(0.82±0.10),差异均有统计学意义(P<0.01),模型组与SASP组(0.73±0.09)比较,差异无统计学意义(P>0.05);Atoh1蛋白、Cdx2蛋白表达,正常组0.48±0.06、0.78±0.08,TUDCA组0.72±0.09、0.58±0.09,均高于模型组(0.32±0.09、0.37±0.07),差异有统计学意义(P<0.01),模型组与SASP组Atoh1(0.30±0.10)比较,差异无统计学意义(P>0.05)。结论 TUDCA和SASP组均可有效减轻小鼠结肠炎模型的炎症反应,两药可能存在协同作用,联合用药效果更优。TUDCA干预机制可能与调节炎性因子,抑制Hes1蛋白激活、增加Cdx2蛋白表达有关。Objective To observe the effects of tauroursodeoxycholic acid（TUDCA） combined with sulfasalazine（SASP） on experimental colitis of mice, and discuss the possible intervention mechanism of TUDCA to colitis model. Methods Experimental colitis model of mice were induced by drinking 5% dextran sulfate sodium（DSS）. Mice in drug grouP〈0were given SASP（500mg/kg）, TUDCA（100mg/kg） and TUDCA combined with SASP〈0by gastric gavage. The normal grouP〈0and model grouP〈0were administered with correspondingly 0.9 % saline, once per day for 8 days. The general status in mice, disease activity index（DAI）, colonic length changes and the score of pathological histology were observed and Hes1, Atoh1 and Cdx2 expression in colons were assessed by immunohistochemistry（SP〈0method）. TNF-a and IL-6 expression in serum were assessed by ELISA. Results The DAI of normal group, TUDCA group, SASP〈0grouP〈0and TUDCA/SASP〈0combined grouP〈0was（0.10±0.23）,（2.37±0.46）,（2.17±0.55） and（1.94±0.34）, respectively, the score of injury was（0.00±0.00）,（6.60±1.71）,（6.10±1.45） and（4.5±1.27）, respectively, all were lower than those of model grouP〈0[（3.43±0.47）,（9.40±1.26）] and the differences were statistically significant（P〈0.01）. The expression of TNF-a and IL-6 in protein level of normal grouP〈0was（46.12±8.35） ng/L,（26.89±5.45） ng/L,（56.48±9.02） ng/L,（27.60±4.76） ng/L in TUDCA group,（59.15±11.09） ng/L,（26.42±5.08） ng/L in SASP〈0group, respectively, all were lower than those of model grouP〈0[（70.64±7.93） ng/L,（35.12±3.51） ng/L] and the differences were statistically significant（P〈0.05）. The expression of Hes1 protein in normal grouP〈0and TUDCA grouP〈0was（0.26±0.12） and（0.40±0.10）, respectively, which were lower than that of model group（0.82±0.10） with statistically significant differences（P〈0.01）. No statistically significant difference was found between model grouP〈0and SASP〈0g

关 键 词：牛磺熊去氧胆酸 结肠炎 发状分裂相关增强子-1 尾型同源盒转录因子-2 

分 类 号：R453[医药卫生—治疗学]