摘要目的 探讨不同质子泵抑制剂(PPI)对大鼠非甾体类抗炎药(NSAID)所致小肠损伤是否具有保护作用及可能的保护机制.方法 将72只SD大鼠均分为空白对照组、模型对照组和奥美拉唑治疗组、埃索美拉唑治疗组、雷贝拉唑治疗组、兰索拉唑治疗组.除空白对照组外其余各组予双氯芬酸7.5mg· kg-1 ·d-1灌胃,1次／d,制备NSAID相关性小肠损伤大鼠模型.各治疗组分别予奥美拉唑30mgmg·kg-1 ·d-1、埃索美拉唑30mg· kg-1·d-1、兰索拉唑45mg·kg-1·d-1、雷贝拉唑15mg· kg1·d1,1次／d灌胃.连续给药5d,处死后取小肠组织,观察其大体和病理学损伤变化,应用Western印迹检测、实时PCR分析小肠组织转录因子红细胞系-2p45相关因子-2(Nrf2)蛋白及mRNA表达,免疫组织化学染色行小肠组织Nrf2的定性及定位分析,黄嘌呤氧化酶法和硫代巴比妥法检测小肠组织超氧化物歧化酶(SOD)和丙二醛(MDA)活性.结果 实验造模成功率100％.空白组对照组大鼠存活率为12/12;模型对照组存活率为9/12；奥美拉唑治疗组存活率为10/12;埃索美拉唑治疗组存活率为11/12;雷贝拉唑治疗组存活率为11/12；兰索拉唑治疗组存活率为10/12.雷贝拉唑、埃索美拉唑、兰索拉唑治疗组大体和病理损伤积分均明显低于模型对照组(P＜0.05).小肠组织SOD活性雷贝拉唑治疗组明显高于模型对照组(P＜0.05),而MDA活性雷贝拉唑、埃索美拉唑治疗组明显低于模型对照组(P＜0.05).Western印迹检测显示雷贝拉唑治疗组小肠组织Nrf2蛋白表达量较模型对照组升高(P＜0.05).实时PCR结果雷贝拉唑治疗组小肠组织Nrf2 mRNA表达较空白对照组和模型对照组明显升高(P值分别＜0.01和0.05).结论 不同PPI对NSAID小肠损伤的保护作用不同,但奥美拉唑的保护作用不明显.其中雷贝拉唑防止NSAID小肠损伤的机制可能通过上调转录因子Nrf2的表达及促进其活化来实现.

abstractsObjective To explore the protective effects and possible mechanism of different type of proton pump inhibitors (PPIs) in non-steroid anti-inflammatory drugs (NSAIDs)induced small intestinal injury.Methods Seventy two SD rats were randomly and equally divided into control group,model group,Omeprazole treated group,Esomeprazole treated group,Rabeprazole treated group and Lansoprazole treated group.Except control group,rats of other groups were gavaged with diclofenac 7.5 mg · kg-1 · d-1,once daily to make NSAIDs related small intestinal injury model.The treated groups were gavaged with Omeprazole 30 mg · kg1 · d-1,Esomeprazole 30 mg· kg1 · d-l,Lansoprazole 45 mg · kg1 · d-1 and Rabeprazole 15 mg · kg-1 · d-1 once daily respectively.Continuous administration for five days and then executed,small intestinal tissues were taken and observed for gross and pathological changes.The expression level of nuclear factor erythroid-2-related factor 2(Nrf2) at protein and mRNA level were detected with western blot and real time PCR assay.The qualitative and location of Nrf2 in small intestinal tissue were analyzed by immunohistochemistry staining and the activity of superoxide dismutase (SOD) and malondialdehyde (MDA) in small intestinal tissue were determined with xanthine oxidase method and TBA respectively.Results The successful rate of modeling experiment was 100％.The survival ratio of control group rats,model group,Omeprazole treated group,Esomeprazole treated group,Rabeprazole treated group and Lansoprazole treated group was 12/12,3/12,2/12,1/12,1/12 and 2/12 respectively.The tissue injure scores of Esomeprazole treated group,Rabeprazole treated group and Lansoprazole treated group were significantly lower than that of model group (P＜0.05).The activity of SOD in small intestinal of Rabeprazole treated group was obviously higher than that of model group (P＜ 0.05),while the activity of MDA in Rabeprazole and Esomeprazole treated groups were significantly lower than that of model group (P＜0.05).The results of westen blot indicated that the expression of Nrf2in small intestinal tissue was obviously higher in Rabeprazole treated group than in model group (P＜0.05).The real time PCR results suggested that the expression of Nrf2 at mRNA level in small intestinal tissue of Rabeprazole treated group was obviously higher than those of model and control groups (P＜0.05).Conclusions The protection effects of various PPIs are different in NSAIDs related intestinal injury.There is no obvious protection effect of Omeprazole.Rabeprazole may prevent NSAIDs related intestinal injury by up-regulating expression of Nrf2 and promoting its activation.