选择性环氧合酶-2抑制剂PC407对TNBS诱导的大鼠溃疡性结肠炎的治疗作用  

Therapeutic effects of selective cyclooxygenase-2 inhibitor PC407 on 2,4,6-trinitrobenzene sulfonic acid-induced ulcerative colitis in rats

作　　者：白卉[1] 张邦乐[1] 李宇华[1] 游宇[2] 郭振军[1] 孙阳[1] 梅其炳[1] 

机构地区：[1]中国人民解放军第四军医大学药学系药理学教研室,陕西省西安市710032 [2]中国人民解放军第四军医大学唐都医院神经外科,陕西省西安市710038

出　　处：《世界华人消化杂志》2008年第12期1287-1293,共7页World Chinese Journal of Digestology

摘　　要：目的:观察新型选择性环氧合酶-2抑制剂PC407对2,4,6-三硝基苯磺酸(2,4,6-trinitrobenzene sulfonic acid,TNBS)诱导的大鼠溃疡性结肠炎的疗效并探讨其机制.方法:应用TNBS/乙醇灌肠复制大鼠溃疡性结肠炎模型.实验设正常对照组、模型对照组、塞来昔布阳性对照组(18mg/kg)和PC407治疗组(9,18mg/kg),ig给药,每天1次,共6d,观察稀便出现情况.实验第7天,麻醉大鼠,分离大鼠结肠、脾脏、胸腺,观察各组实验动物体质量变化及结肠组织病理学改变,选用稀便率、结肠指数、溃疡比、胸腺指数和脾脏指数作为衡量治疗效果的指标.采用免疫组织化学方法检测结肠黏膜环氧合酶-2(COX-2)和肿瘤坏死因子α(tumornecrosisfactor-alpha,TNF-α)的变化.结果:与模型组相比,18mg/kgPC407治疗可明显阻止结肠炎大鼠的体质量下降(258.9gvs223.6g,P<0.05),降低稀便发生率(30%vs80%,P<0.01),改善大鼠结肠组织损伤及病理学改变,包括降低结肠指数(5.03±1.26mg/gvs7.60±2.07mg/g,P<0.01)及溃疡比(24.69%±2.83%vs36.13%±9.64%,P<0.01);同时,PC407治疗可对抗结肠炎症引起的胸腺萎缩(1.96±0.48mg/gvs1.08±0.32mg/g,P<0.01)和脾脏肿大(2.85±0.33mg/gvs3.87±0.96mg/g,P<0.01),显著降低结肠炎大鼠结肠黏膜COX-2和TNF-α的阳性表达率(30.6%±7.0%vs67.4%±1.2%,19.5%±3.0%vs52%±4.7%,P<0.01).9mg/kgPC407也可以改善以上指数,只是作用没有18mg/kg明显.结论:PC407对TNBS/乙醇诱导的大鼠溃疡性结肠炎治疗作用良好,其机制可能通过下调COX-2及TNF-α的表达,从而缓解结肠炎症.AIM： To explore the therapeutic effects of a new selective cyclooxygenase-2 （COX-2） inhibitor PC407 on rat ulcerative colitis induced by 2,4,6-trinitrobenzene sulfonic acid （TNBS） and its possible mechanism. METHODS： A rat colitis model was induced by TNBS and ethonal enema. The rats were randomly divided into 5 groups： normal group, model control group, celecoxib group （18 mg/ kg） and PC407 groups （9, 18mg/kg）. Celecoxib and PC407 were administered intragastrically once per day for 6 days and the loose stool were recorded. All the rats were anesthetized to separate colon, thymus gland and spleen on the 7th day. The body weights of experimental rats before anesthesia were documented and the macroscopic and histological changes of the colon were observed. The effects in treatment groups were evaluated by loose stool rate, colon index, ulcer ratio, thymus index and spleen index. The protein products of COX-2, tumor necrosis factor-α （TNF-α） in mucosa were analyzed by immunohistochemistry. RESULTS： In comparison with that in model control group, the body weight was increased significantly in 18 mg/kg-PC407 group （258.9 g vs 223.6 g, P 〈 0.05）, but the loose stool rate was decreased markedly （30% vs 80 %, P 〈 0.01）; moreover, 18 mg/kg PC407 significantly ameliorated the lesions and pathological changes in colon caused by TNBS, improved the indexes such as colon index （5.03±1.26 mg/g vs 7.60±2.07 mg/g, P 〈 0.01）, ulcer ratio （24.69% ±2.83% vs 36.13%±9.64%, P 〈 0.01）, thymus index （1.96±0.48 mg/g vs 1.08±0.32 mg/g, P 〈 0.01） and spleen index （2.85±0.33 mg/g vs 3.87±0.96 mg/g, P 〈 0.01）, and down-regulated the colonic mucosal expression of COX-2 （30.6%±7.0% vs 67.4%±1.2%, P 〈 0.01） and TNF-α （19.5%±3.0% vs 52%±4.7%, P 〈 0.01）. PC407 at a dose of 9 mg/kg also could improve the above indexes, but the effects were less than PC407 at 18 mg/kg. CONCLUSION： PC407 has significant therapeutic effects on TNBS-induced colitis in rats, and

关 键 词：选择性环氧合酶-2抑制剂 溃疡性结肠炎 2 4 6-三硝基苯磺酸 免疫组织化学 环氧合酶 肿瘤坏死因子-Α 

分 类 号：R574.62[医药卫生—消化系统] R971.1[医药卫生—内科学]