P38MAPK抑制剂对溃疡性结肠炎大鼠外周血淋巴细胞凋亡及相关调控蛋白的影响  

P38 mitogen-activated protein kinase inhibitor SB203580 promotes peripheral blood lymphocyte apoptosis in rats with colitis

作　　者：李军华[1] 周薇[1] 

机构地区：[1]荆门市第一人民医院消化内科,湖北省荆门市448000

出　　处：《世界华人消化杂志》2014年第5期668-673,共6页World Chinese Journal of Digestology

基　　金：湖北省荆门市科学技术计划基金资助项目;No.08S11~~

摘　　要：目的:观察p38丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)特异性抑制剂SB203580对大鼠实验性结肠炎(ulcerative colitis,UC)外周血淋巴细胞(peripheral blood lymphocyte,PBL)凋亡及相关调控蛋白的影响,探讨P38MAPK通路在UC中的可能作用及机制.方法:45只健康SD大鼠随机均分为正常对照组、结肠炎模型组、SB203580组.模型组及SB203580组以三硝基苯磺酸(2,4,6-trinitrobenzene sulfonic acid,TNBS)制备大鼠溃疡性结肠炎模型,正常对照组给予等量0.9%生理盐水灌肠,SB203580组于造模完成后给予1 mg/(kg·d)SB203580腹腔注射.流式细胞仪技术检测PBL凋亡率及Bcl-2表达率,免疫组织化学方法检测活化转录因子-2(phosphoractivating transcription factor 2,p-ATF2)表达;同时观察大鼠疾病活动指数(disease activity index,DAI)、肠道大体形态及组织学评分情况;分析p-ATF2水平与PBL凋亡率及Bcl-2达率的相关关系.结果:与正常组相比,模型组大鼠肠组织磷酸化p-ATF2及PBL中Bcl-2阳性表达显著增高(43.40%±2.67%vs 7.45%±1.26%,38.60%±3.53%vs 13.70%±2.45%,P<0.01),PBL凋亡率明显降低(27.70%±3.02%vs 58.70%±3.09%,P<0.01);SB203580组p-ATF2、Bcl-2阳性表达率较模型组明显下降(20.70%±2.79%,20.30%±2.87%,P<0.01),PBL凋亡率较模型组明显上升(46.60%±4.14%,P<0.01).大鼠DAI及肠道大体形态、组织学评分模型组明显高于正常组(2.42±0.30 vs 0.28±0.29,5.42±0.30 vs 0.30±0.48,3.29±0.26 vs 0.05±0.20,P<0.01),SB203580组较模型组明显下降(1.24±0.17,3.30±0.22,1.10±0.74,P<0.01).结论:P38MAPK抑制剂SB203580通过下调p-ATF2活性及Bcl-2表达,促进PBL的凋亡减轻UC大鼠肠道炎症损伤,对UC具有保护作用.AIM： To investigate the influence of p38 mitogenactivated protein kinase inhibitor SB203580 on peripheral blood lymphocyte （PBL） apoptosis in rats with colitis and the possible mechanisms involved. METHODS： Forty-five healthy female Sprague- Dawley （SD） rats were randomly divided into three groups： a normal group, a model group and a SB203580 group. Colitis was induced with 2,4,6-trinitrobenzene sulfonic acid （TNBS） in rats of the latter two groups. The normal group and the model group were treated intrarectally with saline, while the SB203580 group was given SB203580 [1 mg/（kg·d）]. The rats were sacririced after 2 wk to assess disease activity index （DAI） and macroscopic and histological changes of the colon. PBL apoptosis and Bcl-2 expression were examined by flow cytometry, p-ATF2 pro- tein expression in colon tissue was determined by immunohistochemistry. RESULTS： In the model group, the percentages of cells expressing p-ATF2 and Bcl-2 were higher than those in the normal group and SB203580 group （43.40% ± 2.67% vs 7.45% ± 1.26%, 20.70% ± 2.79%; 38.60% ± 3.53% vs 13.70% ±2.45%, 20.30% ± 2.87%, P 〈 0.01 for all）, but the percentage of apoptotic PBLs in the model group was lower than those in the normal group and SB203580 group （27.70% ± 3.02% vs 58.70% ± 3.09%, 46.60% ± 4.14%, P 〈 0.01 for both）. DAI and macroscopic and histological scores in the model group were significantly higher than those in the normal group and SB203580 group （2.42 ± 0.30 vs 0.28 ± 0.29, 1.24 ± 0.17; 5.42 ± 0.30 vs 0.30 ± 0.48, 3.30 ± 0.22; 3.29 ± 0.26 vs 0.05 ± 0.20, 1.10 ± 0.74, P 〈 0.01 for all）. CONCLUSION： P38MAPK inhibitor SB203580 reduces colonic inflammatory injury in rats with colitis by down-regulating expression of p-ATF2 and Bcl-2 and inducing PBL apoptosis. SB203580 can be considered as a novel therapeutic alternative for the treatment of UC.

关 键 词：溃疡性结肠炎 P38丝裂原活化蛋白激酶 BCL-2 外周血淋巴细胞 凋亡 

分 类 号：R574.62[医药卫生—消化系统]