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肠三叶因子对非酒精性脂肪性肝炎大鼠回肠黏液屏障的影响
Effect of trefoil factor 3 on intestinal mucous barrier in rats with nonalcoholic steatohepatitis
文章发布日期:2017年07月07日  来源:  作者:梁凯,孔维宗,陈娟,等  点击次数:356次  下载次数:37次

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【摘要】:目的 研究非酒精性脂肪性肝炎(NASH)大鼠肠道黏液屏障改变,探讨肠三叶因子(TFF3)对NASH大鼠肠道黏液屏障的影响,及其对NASH的治疗作用。方法 将清洁级雄性SD 大鼠60只随机分为正常组、模型组和治疗组,每组20只。正常组给予普通饲料,模型组和治疗组给予高脂饲料12周,诱导NASH模型后,治疗组给予rhTFF3 1 ml·kg-1·d-1(浓度0.1 mg/ml)腹腔内注射,正常组与模型组给予1 ml·kg-1·d-1生理盐水,连续3周。第15周末,FITC标记的右旋糖酐灌胃检测大鼠回肠通透性后,处死大鼠,检测血清AST、ALT、TC、TG、内毒素(ET)水平及二胺氧化酶(DAO)活性。HE染色观察肝脏和回肠末端组织病理变化,PAS染色观察回肠末端杯状细胞并计数,免疫组化方法检测回肠末端紧密连接蛋白Occludin和TFF3 蛋白表达水平,实时荧光定量PCR检测TFF3 mRNA转录水平。多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。结果 大鼠血清 AST、ALT、TG、TC、DAO、ET水平在模型组升高,而治疗组较模型组明显下降(P值均<0.01);模型组NAS评分较正常组显著增高(P<0.01),而治疗组肝组织炎症改善,NAS评分较模型组明显降低(P<0.01);光镜下模型组回肠末端细胞坏死,绒毛损伤,杯状细胞明显减少,治疗组绒毛损伤修复,杯状细胞增多;模型组大鼠回肠通透性与正常组比显著增加,治疗组较模型组明显降低(P值均<0.01);Occludin和TFF3在模型组表达减少,而治疗组较模型组增多(P值均<0.01);回肠末端TFF3 mRNA转录水平模型组较正常组下调,治疗组表达较模型组上调(P值均<0.01)。结论 NASH大鼠存在肠道杯状细胞损伤,黏液屏障功能障碍,TFF3可以修复回肠末端损伤,促进杯状细胞再生与黏液分泌,修复肠屏障功能,降低肠通透性,对NASH起到治疗作用。
【Abstract】:Objective To investigate the change in intestinal mucous barrier in rats with nonalcoholic steatohepatitis (NASH), the effect of trefoil factor 3 (TFF3) on intestinal mucous barrier in NASH rats, and the therapeutic effect of TFF3 on NASH. Methods A total of 60 clean male Sprague-Dawley rats were randomly divided into normal group, model group, and treatment group, with 20 rats in each group. The rats in the normal group were given normal diet, and those in the model group and the treatment group were given high-fat diet to induce NASH. The rats in the treatment group were given intraperitoneal injection of rhTFF3 at a dose of 1 ml/kg/d (a concentration of 0.1 mg/ml), and those in the normal group and the model group were given normal saline at a dose of 1 ml/kg/d; the course of treatment was 3 weeks for all groups. At the end of week 15, fluorescein isothiocyanate-labeled dextran was given by gavage to evaluate intestinal permeability, and after the rats were sacrificed, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), and endotoxin (ET) and diamine oxidase (DAO) activity were measured. HE staining was performed to observe the histopathological changes of the liver and the terminal ileum, PAS staining was performed to observe and count the goblet cells of the terminal ileum, immunohistochemistry was used to measure the expression of the tight junction protein Occludin and TFF3 in the terminal ileum, and quantitative real-time PCR was used to measure the mRNA transcription level of TFF3. A one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between any two groups. Results The model group had significant increases in serum levels of AST, ALT, TC, TG, and ET and DAO activity, and the treatment group had significant reductions compared with the model group (all P<0.01). The model group had a significant increase in NAFLD activity score compared with the normal group (P<0.01), and the treatment group had significant improvement in liver inflammation and a significant reduction in NAFLD activity score compared with the model group (P<0.01). The model group had cell necrosis, damage of the intestinal villi, and a significant reduction in goblet cells in the terminal ileum under a light microscope; in the treatment group, damage of the intestinal villi was repaired and there was an increase in goblet cells. The model group had a significant increase in intestinal permeability compared with the normal group, and the treatment group had a significant reduction compared with the model group (both P<0.01). The model group had a significant reduction in the expression of Occludin and TFF3, and the treatment group had a significant increase compared with the model group (all P<0.01). The model group had a downregulated TFF3 mRNA transcription level in the terminal ileum compared with the normal group, and the treatment group had an upregulated level compared with the model group (both P<0.01). Conclusion NASH rats have damaged goblet cells and mucous barrier dysfunction. TFF3 can repair the damaged terminal ileum, promote the regeneration of goblet cells and mucus secretion, restore intestinal barrier function, reduce intestinal permeability, and thus exert its therapeutic effect on NASH.
【关键字】:脂肪肝;肠三叶因子;杯状细胞;大鼠,Sprague-Dawley
【Key words】:fatty liver; trefoil factor 3; goblet cells; rats, Sprague-Dawley
【引证本文】:梁凯, 孔维宗, 陈娟, 等. 肠三叶因子对非酒精性脂肪性肝炎大鼠回肠黏液屏障的影响[J]. 临床肝胆病杂志, 2017, 33(8): 1552-1557.

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