尼美舒利抑制乙基硝基亚硝基胍诱导大鼠胃癌癌前病变的作用机制

目的:探讨选择性环氧合酶-2(COX-2)抑制剂尼美舒利在乙基硝基亚硝基胍(ENNG)诱导大鼠胃癌癌前病变发展过程的作用以及可能机制.方法:6周龄♂Wistar大鼠给予浓度为100 mg/L的ENNG溶液饮用14 wk后,使用浓度为300 m g/L和1 200 mg/L的尼美舒利溶液由大鼠自由饮用,分别在喂养14、26和38 wk后观察大鼠胃黏膜病变.使用免疫组织化学的方法观察大鼠病变胃黏膜COX-2蛋白、Bcl-2蛋白以及PCNA的表达,TUNEL法检测大鼠胃黏膜细胞凋亡.结果:药物干预的大鼠胃癌癌前病变的发生率显著低于对应的非用药组(P<0.05);药物干预组大鼠病变胃黏膜的COX-2蛋白和Bcl-2蛋白表达分别为17.6%,35.3%,显著低于非用药组的60%和84%(P<0.05);增殖指数18.9±4.57显著低于非用药组49.43±7.92(P<0.05);凋亡指数13.6±1.82显著高于非用药组2.12±0.53(P<0.05);COX-2蛋白和Bcl-2蛋白与PCNA的表达以及凋亡指数具有相关性(P<0.01).结论:选择性COX-2抑制剂尼美舒利能有效抑制ENNG诱导的大鼠胃癌癌前病变的发展,其机制可能是通过抑制COX-2、Bcl-2蛋白的表达,从而抑制病变胃黏膜细胞的增殖以及诱导其凋亡.

Inhibitory effect of nimesulide on the development of N-ethyl-N-nitro-N-nitrosoguanidine-induced gastric precancerous lesions in rats

AIM: To investigate the inhibitory effect of nimesulide,a selective cyclooxygenase(COX)-2 inhibitor,on the development of N-ethyl-N-nitro-N-nitrosoguanidine(ENNG)-induced gastric precanerous lesions in rats. METHODS: Six-week-old male Wistar rats were given 100 mg/L of ENNG in their drinking water for 14 wk and then fed a diet containing nimesulide at doses of 300 mg/L and 1200 mg/L for 12 or 24 wk.The rats were sacrificed 14,26 and 38 wk after nimesulide feeding to detect the changes in the gastric mucosa.The expression of COX-2,Bcl-2 and PCNA in the gastric mucosa was detected by immunohitochemistry,and cell apoptosis was determined using TUNEL assay. RESULTS: Nimesulide significantly reduced the incidence of gastric precancerous lesions compared to controls(P < 0.05).The positive rates of COX-2 and Bcl-2 protein expression and proliferation index in the nimesulde group were significantly lower than those in the control group(17.6% vs 60%,35.3% vs 84%,18.9 ± 4.57 vs 49.43 ± 7.92,all P < 0.05),while the apoptotic index was significantly higher in the nimesulde group than in the control group(13.6 ± 1.82 vs 2.12 ± 0.53,P < 0.05).The expression of COX-2 and Bcl-2 protein was associated with proliferation index and apoptotic index(P < 0.01). CONCLUSION: Nimesulide has inhibitory effects on the development of ENNG-induced gastric precancerous lesions in rats possibly via mechanisms associated with reducing COX-2 and Bcl-2 expression,inhibiting proliferation and inducing apoptosis of gastric epithelial cells.