加贝酯对大鼠小肠缺血再灌注损伤保护作用的实验研究

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1、硕士学位论文加贝酯对大鼠小肠缺血再灌注损伤保护作用的实验研究院（系）、所临床医学院研究生姓名谢云飞学科、专业外科学导师姓名徐亮教授二Ο一二年五月目录加贝酯对大鼠小肠缺血再灌注损伤保护作用的实验研究11.1中文摘要„„„„„„„„„„„„„„„„„„„„„11.2英文摘要„„„„„„„„„„„„„„„„„„„„„31.3前言„„„„„„„„„„„„„„„„„„„„„„„61.4材料与方法„„„„„„„„„„„„„„„„„„„„81.5结果„„„„„„„„„„„„„„„„„„„„„„„171.6讨论„„„„„„

2、„„„„„„„„„„„„„„„„„221.7结论„„„„„„„„„„„„„„„„„„„„„„„311.8参考文献„„„„„„„„„„„„„„„„„„„„„321.9英汉缩略词对照表„„„„„„„„„„„„„„„„„372综述„„„„„„„„„„„„„„„„„„„„„„„383加贝酯对大鼠小肠缺血再灌注损伤保护作用的实验研究摘要目的：广谱的蛋白酶抑制剂加贝酯(gabexatemesilate,GM)作为一种新型酶抑制剂，可抑制多种蛋白酶，对舒血管素、胰蛋白酶、纤维蛋白酶、酯酶C1、磷酯酶A2均有抑制作用，抑制

3、炎性介质的释放。通过研究加贝酯对大鼠小肠缺血再灌注后小肠粘膜的损伤程度影响，对小肠缺血再灌注后(ischemia/ruperfusion，IR)小肠粘膜TNF-a、IL-6、丙二醛（MDA）表达的影响，为小肠缺血再灌注损伤提出新的治疗思路。方法：健康成年SD大鼠42只，体重在280g-320g之间，均为雄性，随机分为对照组、缺血再灌注（IR）组和加贝酯干预组。以脱毛剂脱去腹毛发，常规消毒铺巾后取上腹部正中切口长约2-3cm，进入腹腔后快速分离肠系膜上动脉(SMA)。对照组分离SMA后即关腹，45分钟后再次开

4、腹后关腹，不做其它处理。缺血再灌注组以无创动脉夹夹闭SMA,45min后移去动脉夹行再灌注。加贝酯组夹闭SMA45min后行再灌注，在再灌注前40min经尾静脉注入加贝酯(10mg/kg·h)。分别于再灌注2小时采集标本。小肠组织HE染色后病理学检测，采集腹主动脉血液用ELISA法检测大鼠血清TNF-a、IL-6含量，在活体情况下距回盲部切取小肠3cm左右，测定MDA的基础含量。结果:(l)肠粘膜病理变化:对照组大鼠小肠绒毛完整，无明显出血及脱落,无明显炎症细胞浸润及毛细血管扩张、淤血。IR组大鼠的小肠绒毛

5、上皮与固有层分离，固有层出血，大量炎性细胞浸润，粘膜绒毛坏死脱落。加贝酯干预组肠粘膜绒毛损伤较轻，小肠粘膜毛细血管轻度扩张、淤血，1部分上皮下间隙增大炎性细胞浸润较少，可见上皮层与固有层分离。对照组、IR组和加贝酯组的病理评分Chiu氏评分值分别为：0.92±0.55、4.21±0.51、2.42±0.54，各组经检验具有统计学差异p<0.05。(2)细胞因子变化:对照组、IR组和加贝酯组缺血再灌注后2小时大鼠血清中细胞因子TNF-a分别为：25.60±2.58pg/ml、73.49±24.90pg/ml、

6、42.23±13.48pg/ml，各组经检验具有统计学差异p<0.05。大鼠血清中细胞因子IL-6分别为：16.31±3.13pg/ml70.23±23.70pg/ml34.69±13.56pg/ml，各组经检验具有统计学差异p<0.05。(3)对照组、IR组和加贝酯组缺血再灌注后2小时大鼠肠组织中的MDA含量分别为：3.20±0.73nmol/mgprot、10.47±1.30nmol/mgprot、4.96±0.82nmol/mgprot，各组经检验具有统计学差异p<0.05。结论：(l)加贝酯能有效减

7、轻大鼠肠缺血再灌注所致的小肠粘膜病理损伤程度:小肠粘膜绒毛的坏死程度，减少绒毛脱落，减少中性粒细胞的浸润，减轻粘膜内出血，减少溃疡形成。(2)加贝酯可抑制缺血再灌注后脂质氧化反应，降低大鼠小肠组织MDA含量，对小肠缺血再灌注损伤有保护作用。(3)加贝酯能减少大鼠小肠缺血再灌注损伤促炎细胞因子TNF-a、IL-6的释放，减轻小肠炎症反应导致的损伤。关键词：小肠，大鼠，缺血再灌注损伤，加贝酯2ExPerimenta1StudyofgabexatemesilateProtectsAgainstSma11intes

8、tina1ischemia-Reperfus1oninjuryInRatsAbstraetAbstract:Objective:abroad-spectrumproteaseinhibitorgabexatemesilate(GM)asanewtypeofenzymeinhibitors,caninhibitavarietyofproteases,thevasodilatorypeptide,trypsin,fi