瑞巴派特对阿司匹林诱导的小鼠小肠上皮屏障损伤的修复

Rebamipide repairs injury of small intestinal epithelial barrier induced by aspirin in mice

目的:探讨瑞巴派特能否通过促进肠道上皮屏障结构和功能的修复改善阿司匹林导致的小肠黏膜损伤。方法:本研究利用BALB/c小鼠,使用阿司匹林(200 mg·kg^(-1)·d^(-1))连续5 d灌胃的方法制作小肠损伤模型,并根据是否诱导小肠损伤及接受瑞巴派特(320 mg·kg^(-1)·d^(-1))的处理将小鼠分为正常对照组、模型组、瑞巴派特对照组及瑞巴派特治疗组。通过透射电镜、免疫组化、qPCR和Western blot等方法,在不同时点系统地观察瑞巴派特对阿司匹林所致的小鼠小肠黏膜损伤模型中小肠黏膜结构及屏障功能蛋白表达的影响。结果:阿司匹林所致的小肠黏膜损伤小鼠,经瑞巴派特(320 mg·kg^(-1)·d^(-1))连续5 d处理后,小肠上皮细胞间紧密连接结构的损害明显减轻,小肠组织中紧密连接蛋白ZO-1及occludin在mRNA及蛋白质水平的表达均明显增加(P<0.05),环氧化酶2(COX-2)和增殖相关信号分子β-catenin、c-Myc的表达也高于对照组(P<0.05),组织匀浆中前列腺素E_2浓度显著增加(P<0.05),而COX-1的表达在治疗组中无明显改变。同时,治疗组血清中的D-乳酸水平明显降低(P<0.05)。结论:瑞巴派特能够通过上调COX-2的表达,促进阿司匹林所致的小鼠小肠黏膜损伤的修复,改善肠屏障的结构与功能。

AIM： To investigate whether rebamipide repairs the small intestinal epithelial barrier in aspirin-induced small intestinal injury（ SII） in mice and its mechanism. METHODS： Small intestinal injury was induced by aspirin（200 mg·kg^（-1）·d^（-1）for 5 d） in BALB/c mice. Based on the treatment with aspirin and/or rebamipide（ 320 mg ·kg^（-1）·d^（-1））,the mice were divided into 4 groups（n = 18 in each group）. The living mice in each group（n = 6） were sacrificed via cervical dislocation method at day 0,day 5,and day 10. The structure and function of intestinal barrier and the levels of the signaling pathway factors were measured by transmission electron microscopy,immunohistochemistry,q PCR,and Western blot. RESULTS： Tight junctions between intestinal epithelial cells improved significantly after rebamipide treatment. The expression of ZO-1 and occludin in the injured small intestine showed a gradually increasing trend after rebamipide administration（ P 0. 05）. There was a decreased trend of D-lactate level in rebamipide-treated SII mice（P 0. 05）. The expression of cyolooxygenase-2（COX-2）,β-catenin,and c-Myc,and prostaglandin E_2 concentration in small intestinal tissues were significantly increased in rebamipide treatment group（ P 0. 05）. However,down-regulated COX-1 expression in the SII mice was sustained at a low level after rebamipide administration. CONCLUSION： Rebamipide repairs the injury of small intestinal mucosa and improves the structure and function of small intestinal barrier in aspirininduced SII mice by up-regulating the expression of COX-2.