胃十二指肠反流物对实验鼠食管的致癌性研究

Carcinogenesis effects of gastric and duodenal refluxate on esophageal mucosa

目的 通过动物实验、病理学研究及肿瘤相关基因检测探讨胃及十二指肠内容物反流对食管肿瘤发生过程的影响。方法 健康SD大鼠 2 10只 ,运用不同手术方式制作单纯胃食管反流 (G组 )、单纯十二指肠食管反流 (D组 )、十二指肠胃混合食管反流 (DG组 )及无反流对照组 (C组 )动物模型。术后均注射致癌剂甲基戊基亚硝胺 (MANA) ,于不同时期取出食管组织进行形态学研究 ,并用免疫组化法检测组织中p5 3、细胞周期蛋白 (cyclin)D1、细胞周期蛋白依赖性激酶 4(CDK4 )等基因的表达。结果 术后 4周 (未予致癌剂时 )各反流组即出现食管黏膜损伤的表现 ,病变程度D组 >DG组 >G组 ,C组无异常。随时间延长各组病变逐渐加重。术后 40周D、DG、G组大鼠乳头状瘤发生率分别为 94 7%、95 2 %、70 5 % ,与C组 (38 5 % )相比P值均 <0 0 5 ;D组及DG组共发现 2 4例柱状上皮化生、2 0例异型增生、11例食管癌 ,发生率显著高于G组、C组。D组、DG组大鼠的食管组织中p5 3、cyclinD1、CDK4 基因表达明显增强 ,显著高于G组 ,各组与C组相比差异均有显著性。结论 胃及十二指肠反流均可损伤食管黏膜 ,并通过改变细胞周期调控蛋白的表达而加重对食管的致癌作用 ,其中十二指肠内容物的作用更强 。

Objective To investigate the effects of different refluxant on esophageal carcinogenesis in rats. Methods The animal models of gastroesophageal reflux(G), duodenoesophageal reflux(D) and duodenogastroesophageal reflux(DG) and no reflux as control (C) were made by operations. The rats in all of the groups were given carcinogen (methyl-n-amyl nitrosamine, MANA).They were killed at 4,20,26,40-week,then their esophagi were taken to the morphologic study and the expression of p53,cyclinD 1,CDK 4 studied with immunohistochemical studies. Results At 4-week without carcinogen ,most of rats in reflux groups displayed evidence of esophageal mucosal injury. The degree of mucosal injury in D group was greater than that in DG which was greater than that in G; and became severity with the time. At 40 weeks, the incidences of papillomas in group D,DG,G were 94.7%, 95.2%, 70.5%,respectively. All of them compared to the group C(38.5%) were significant difference. Only in both D and DG group ,there were 24 with esophageal columnar metaplasia, 20 with dysplasia and 11 with cancer. The overexpression of p53、CDK 4、cyclin D 1 was seen in D and DG groups, while in G group , the overexpression of p53 and cyclin D 1 were seen only. Conclusion Both of gastric juice and duodenal contents reflux can promote tumourgenesis of MANA on esophagi by changing the expression of cell cycle-related protein. The effect of duodenal contents is stronger. It may play an important role in tumourgenesis of gastroesophageal reflux disease.