罗格列酮对大鼠溃疡性结肠炎肠黏膜NF-κB,ICAM-1表达的影响

Effects of rosiglitazone on expression of NF-κB and ICAM-1 in rats with ulcerative colitis

目的:探讨罗格列酮对大鼠溃疡性结肠炎肠黏膜核转录因子-κB(NF-κB),细胞间黏附分子-1(ICAM-1)表达的影响.方法:应用三硝基苯磺酸(TNB)/乙醇灌肠制备大鼠溃疡性结肠炎模型.实验设正常对照组,模型对照组,阳性药物组(柳氮磺吡啶SASP组,100mg/kg),罗格列酮组(2,4,8mg/kg),每天灌胃给药1次,给药时间从造模后第2天开始至实验结束共8d,观察大鼠疾病活动指数(DAI)和结肠黏膜损伤指数(CMDI),生化法检测大鼠结肠组织髓过氧化酶(MPO)活性,免疫组化法检测大鼠肠黏膜NF-κBp65和ICAM-1蛋白的表达.结果:与正常组相比,模型组DAI、CMDI评分及结肠组织MPO活性明显升高(2.11±1.29vs0.11±0.17,2.67±0.82vs0.33±0.52,1.26±0.36U/gvs0.27±0.07U/g,P<0.01),结肠黏膜NF-κBp65及ICAM-1表达明显增强(0.7081±0.0671vs0.2293±0.0474;0.4846±0.0366vs0.1783±0.0201,P<0.01).罗格列酮中、高剂量组DAI,CMDI评分及MPO活性较模型组有明显下降(DAI:1.11±0.50,0.61±0.25vs2.11±1.29,P<0.05;CMDI:1.67±0.52,1.17±0.75vs2.67±0.82,P<0.05;MPO:0.82±0.13,0.51±0.10U/gvs1.26±0.36U/g,P<0.01),NF-κB及ICAM-1表达也有不同程度降低(NF-κB:0.4544±0.0379,0.2577±0.0131vs0.7081±0.0671,P<0.01;ICAM-1:0.3854±0.0277,0.2830±0.0234vs0.4846±0.0366,P<0.01).大鼠结肠黏膜NF-κB的表达与ICAM-1表达呈正相关(r=0.927,P<0.01),ICAM-1的表达与结肠组织MPO活性也呈正相关(r=0.580,P<0.01).结论:罗格列酮对大鼠溃疡性结肠炎有保护作用,其作用机制可能与抑制NF-κB活化,减少黏附分子ICAM-1产生以及降低中性粒细胞浸润有关.

AIM： To investigate the effect of rosiglitazone on the expression of nuclear factor-kappa B （NF-κB） and intercellular adhesion molecule-1 （ICAM-1） in the colon mucosa of rats with ulcerative colitis. METHODS： The rat colitis model was induced by the combined enema of trinitrobenzene sulphonic acid （TNB） and ethanol. The experimental animals were randomly divided into six groups： normal group, model group, Sulfasalazine （SASP） group （100 mg/kg）, and 3 rosiglitazone groups （2, 4, 8 mg/kg）. The saline, SASP, and different concentrations of rosiglitazone were administered by gastric irrigation daily, respectively, from 24 h after the establishment of model to the end of experiment. The disease activity index （DAI） and colon mucosa damage index （CMDI） of the rats were observed and evaluated. The activity of myeloperoxidase （MPO） was measured by biochemical method. The expression of NF-κBp65 and ICAM-1 protein were detected by immunohistochemistry. RESULTS： As compared with the normal group, the DAI, CMDI, and the activity of MPO in the colon tissues of the rats in the model group were significantly increased （2.11 ± 1.29 vs 0.11 ± 0.17; 2.67 ± 0.82 vs 0.33 ± 0.52; 1.26 ± 0.36 U/g vs 0.27 ± 0.07 U/g; all P 〈 0.01）. The expression of NF-κBp65 and ICAM-1 in the rat colon mucosa were significantly increased （0.7 081 ± 0.0 671 vs 0.2 293 ± 0.0 474; 0.4 846 ± 0.0 366 vs 0.1 783 ± 0.0 201, both P 〈 0.01）. The DAI, CMDI, and the activity of MPO in the 4 mg/kg and 8 mg/kg rosiglitazone group were significantly decreased （DAI： 1.11 ± 0.50, 0.61 ± 0.25 vs 2.11 ± 1.29, P 〈 0.05; CMDI： 1.67 ± 0.52, 1.17 ± 0.75 vs 2.67 ± 0.82, P 〈 0.05; 0.82 ± 0.13, 0.51 ± 0.10 U/g vs 1.26 ± 0.36 U/g, P 〈 0.01） in comparison with those in the model group, and the expression of NF-κB and ICAM-1 were also decreased （NF-κB： 0.4 544 ± 0.0 379, 0.2 577 ±0.0 131 vs 0.7 081 ± 0.0 671, P 〈 0.01; ICAM-1： 0.3 854 ± 0.0 277, 0.2 830 ± 0.0 234 vs 0.4 846 ± 0.0 366, P 〈 0.01）. The expression of NF-κBp65 and ICAM-1 in rat colon mucosa was positively correlated （r = 0.927, P 〈 0.01）, and the expression of ICAM-1 and the activity of MPO was also positively correlated with each other （r =0.580, P 〈 0.01）. CONCLUSION： Rosiglitazone has protective effect against rat ulcerative colitis, and its mechanism may be related with the inhibition of the NF-κB activation, reduction of the ICAM-1, and decreasing of neutrophil invasion.