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氧化应激及凋亡与重症急性胰腺炎肠屏障功能障碍

Oxidative stress and apoptosis in gut barrier dysfunction of severe acute pancreatitis

摘要:

目的 通过动物实验,观察重症急性胰腺炎(severe acute pancreatitis,SAP)肠道屏障功能变化,探讨炎症因子释放、肠黏膜氧化应激及凋亡在肠屏障功能障碍中的作用.方法 上海交通大学附属第一人民医院动物实验中心内,24只BALB/c小鼠,随机数字法分为2组,SAP组:以雨蛙素联合脂多糖腹腔注射法诱导,先腹腔内注射雨蛙素50 μg/kg,连续6次,每次间隔1h,在末次雨蛙素注射同时,腹腔内注射脂多糖10 mg/kg(LPS E.Coli);对照(假手术)组:每小时一次腹腔注射生理盐水2 ml,共6次.两组动物分2批(每批6只/组)分别于建模后4h及8h,麻醉后打开腹腔取血及标本.观察小鼠胰腺及肠道病理变化并予评分,测定小鼠血二胺氧化酶(diamine oxidase,DAO)、淀粉酶、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)含量,测定肠黏膜丙二醛( malondialdehyde,MDA)、超氧化物歧化酶(superoxide dismutase,SOD)、还原型谷胱甘肽( glutathione,GSH)含量及黄嘌呤氧化酶(xanthine oxidase,XO)活力,检测小鼠肠黏膜细胞caspase-3酶活性,脱氧核糖核苷酸末端转移酶介导的缺口末端标记(terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling,TUNEL)法检测小鼠肠黏膜凋亡细胞并计算凋亡指数.以PASW 18.0软件对数据进行方差分析及t检验,明确上述检测指标在两组小鼠间差异是否有统计学意义,从而明确重症急性胰腺炎肠道屏障功能障碍的机制.结果 建模后4h及8h,SAP组小鼠胰腺出血、坏死、炎症细胞浸润较对照组严重,胰腺病理评分与对照组比较差异具有统计学意义(P<0.01),血淀粉酶含量与对照组比较差异具有统计学意义(P<0.05);肠组织病理评分及血DAO质量浓度与对照组比较差异具有统计学意义(P<0.01);血TNF-α质量浓度与对照组比较差异具有统计学意义(P<0.01);肠黏膜MDA含量及XO活力与对照组比较差异具有统计学意义(P<0.01),肠黏膜SOD含量与对照组比较差异具有统计学意义(P<0.01)、GSH含量与对照组比较差异具有统计学意义(P<0.05);肠黏膜细胞caspase-3酶活性及凋亡指数与对照组比较差异具有统计学意义(P<0.01).结论 重症急性胰腺炎发病后,TNF-α等炎症因子瀑布样释放,导致肠黏膜缺血-再灌注损伤,形成严重的氧化应激反应,进一步激活caspase-3通路,导致肠黏膜细胞凋亡增加,是肠黏膜屏障功能受损的重要机制.

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abstracts:

Objective By means of animal study,investigated the gut barrier function in severe acute pancreatitis ( SAP),and role of inflammatory factors releasing,gut mucosa oxidative stress,cell apoptosis in it.Methods The animal experiment was done in the animal center of first people' s hospital,shanghai jiaotong university.Twenty four BALB/c mice were randomized ( random number) divided into two groups with twelve mice each group.The SAP group,mice received six intraperitoneal injections of cerulein at 1-hour intervals, the dose was 50μg/kg, then given one intraperitoneal injection of 10 mg/kg lipopolysaccharide ( LPS from E.Coli) for the induction of severe acute pancreatitis.The control ( sham operation) group,the mice received intraperitoneal injection of 2 ml normal saline for six times at 1-hour intervals.All the animals of each group were averaged to two batches,4 h and 8h after being operated respectively,to be anesthetized and adopted blood and tissue specimen.Then we observed the pathological change of pancreas and gut,scored it.We measured the blood value of diamine oxidase ( DAO),amylase and tumor necrosis factor-α (TNF-α).We detected content of malondialdehyde (MDA),superoxide dismutase (SOD),glutathione (GSH) and activity of xanthine oxidase (XO) in gut mucosa.We detected the casepase-3 activity and cell apopotosis by means of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in gut mucosa,and conculated the apopotosis index (AI).Then using the PASW 18.0 software,we analyzed the data by anova and t-test,to make sure if the values were statistically different between the two groups and the mechanism of gut barrier dysfunction in panreatitis.Results At 4 h and 8 h after operation,the SAP-group-mice had significantly higher pancreas pathological score (P <0.01 ),blood amylase value ( P < 0.05 ),gut pathological score and blood DAO and TNF-α value ( P <0.01 ),compared with the contral-group-mice.The gut mucosa MDA content and XO activity of mice in SAP group were significantly higher than which in control group ( P < 0.01 ). The SAP-group-mice had significantly lower gut mucosa SOD content ( P < 0.01 ) and GSH content ( P < 0.05 ),compared with the contral-group-mice.The gut mucosa cells of mice in SAP group had significantly higher caspase-3 activity and apoptosis index than which in control group ( P < 0.01 ).Conclusions In severe acute pancreatitis,inflammatory factors such as TNF-αwere waterfall-style released,induced gut mucosa suffer from ischemia-reperfusion injury,then serious oxidative stress developed in mucosa and activated caspase-3 pathway,inducing gut mucosa cells apoptose seriously,which was an important mechanism of gut barrier dysfunction.

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