氯吡格雷对大鼠急性胃黏膜损伤愈合的影响及机制

目的:研究氯吡格雷对大鼠急性胃黏膜损伤愈合的影响作用及其机制.方法:40只健康♂SD大鼠随机分为4组,每组10只:阴性对照组、单纯损伤组、10mg/kg氯吡格雷处理组、30mg/kg氯吡格雷处理组;以大剂量阿司匹林灌胃制造大鼠急性胃黏膜损伤模型后,对氯吡格雷处理组的大鼠以相应剂量的氯吡格雷进行灌胃处理,给药3d,每天1次.分别测定各组大鼠的胃黏膜损伤指数(lesionindex,LI);观察大鼠胃黏膜组织学变化;免疫组织化学法检测各组紧密连接蛋白Occludin的表达情况;免疫蛋白印迹法(Westernblot)检测紧密连接蛋白Occludin、ZO-1以及MAPK信号通路中磷酸化P38、磷酸化ERK及磷酸化JNK蛋白的表达量.结果:与损伤组相比,氯吡格雷处理组大鼠胃黏膜损伤加重,且30mg/kg组损伤重于10mg/kg组(39.8±5.05vs35.3±3.86,P<0.05);在阴性对照组、单纯损伤组、10mg/kg氯吡格雷处理组、30mg/kg氯吡格雷处理组中,大鼠胃黏膜中的紧密连接蛋白Occludin、ZO-1蛋白的表达逐渐下降,呈递减趋势(P=0.000),而磷酸化P38、磷酸化ERK蛋白表达则逐渐上升,呈递增趋势(P=0.000).结论:氯吡格雷能够抑制大鼠急性胃黏膜损伤的愈合,其可能是通过激活MAPK中的p38和ERK信号通路,下调胃黏膜上皮细胞间紧密连接蛋白Occludin和ZO-1的表达,破坏大鼠胃黏膜的屏障.

Clopidogrel delays the healing of aspirin-induced gastric mucosal lesions in rats

AIM: To determine the effect of clopidogrel on the healing of aspirin-induced gastric mucosal lesions in rats and to explore possible mechanisms involved. METHODS: Forty healthy male SD rats were randomly and equally divided into four groups: normal group, injury group, and two clopidogrel groups (10 mg/kg and 30 mg/kg). Gastric mucosal lesions were induced in rats by oral administration of aspirin (200 mg/kg). Rats of the clopidogrel groups were continuously administrated with clopidogrel for 3 days. After treatment, histological changes were evaluated under a microscope; the distribution of gastric epithelial tight junction protein occludin was determined by immunohistochemistry; and the expression levels of ZO-1, occludin, as well as phosphorylated ERK (p-ERK), P38 (p-P38) and JNK (p-JNK) were determined by Western blot. RESULTS: Compared to the injury group, the lesion indices of the clopidogrel groups were significantly increased (39.8 ± 5.05 vs 35.3 ± 3.86, P <0.05), and the increase was more significant in the high-does group than in the low-dose group (P<0.05). In clopidogrel groups, the expression levels of occludin and ZO-1 were lower in the clopidogrel groups than in the injury group (P<0.05), and in the high-does group than in the low-does group. Activation of P38 and ERK were more obvious in the clopidogrel groups than in the injury group (P<0.05). CONCLUSION: Clopidogrel significantly delays the healing of gastric lesions in rats probably by decreasing the expression of tight junction protein occludin and ZO-1 through the p38 and ERK signaling pathways.