An Experimental Study Of Barrett's Esophagus And Esophageal Adenocarcinoma Induced By Reflux And The Expression And Significance Of Inducible Nitric Oxide Synthase In The Carcinogenesis

Objective 1. To establish a new experimental animal model of esophageal adenocarcinoma in rats induced by the acidic mixed reflux of duodenal and gastric juice which represents the pathophysiology of human gastroesophageal reflux disease better than before. 2. To study the role of gastric acid in the esophageal adenocarcinogenesis induced by duodenal juice reflux in rats. 3. To investigate the expression and significance of inducible nitric oxide synthase (iNOS) in the pathogenesis of Barrett's esophagus and its progression to esophageal adenocarcinoma. Methods The study consists of three parts. Parti, establishment of a new animal model: 65 eight-week-old male Sprague-Dawley (SD) rats underwent end-to-side gastrojejunostomy followed by end-to-side esophagojejunostomy to produce the acidic mixed reflux of duodenal juice and gastric juice in the distal esophagus. Another 10 rats undergoing a sham operative procedure were taken as a control group. The animals were sacrificed and the esophageal samples were taken from the experimental group at week 1, 4, 8, 12, 16, 20 respectively after surgery and from the control group at week 20. Mucosal pathological changes in the esophagus were examined macroscopically and microscopically. Part 2, comparison of the 4effects induced by different components reflux: 110 eight-week-old male SD rats were divided into three groups by different surgical procedures to produce gastric juice reflux(n=30), duodenal juice reflux(n=40) and acidic mixed reflux(n=40), compared with a control group(n=l5). Esophageal mucosal pathological changes were examined macroscopically and microscopically 20 weeks after surgery. Part 3, immunohistochemical examination of iNOS: The expression of iNOS was detected microscopically by immunohistochemical technique in 116 slides from 63 esophageal samples of the experimental rats. Results 1. The incidence of Barrett's esophagus and esophageal adenocarcinoma in the new model increased with time: 33. 3% and 0% at week 8, 62. 5% and 12. 5% at week 12, 90% and 30% at week 16,86. 6% and 53. 3% at week 20. 2. In the duodenal juice reflux and acidic mixed reflux animals , the incidence of Barrett's esophagus was 91. 4% and 84. 4%, and the incidence of esophageal adenocarcinoma was 25.7% and 53.1%. Interestingly, the incidence of esophageal adenocarcinoma in the acidic mixed reflux group was significantly higher than in the duodenal juice reflux group (P<0. 05). 3. Immunohistochemical analysis showed that positive iNOS expression in the stromal macrophages directly beneath the epithelium in the distal one-third of the esophagus was 0%, 0%, 50%, 80%, 100% and 100% of the rats at weeks 1, 4, 8, 12, 16 and 20 respectively. Positive iNOS expression in the cases with Barrett's esophagus or esophageal adenocarcinoma was 100%. Conclusion 1. The new model created in this study can induce a high incidence of Barrett's esophagus and esophageal adenocarcinoma satisfactorily and reliably which are morphologically similar to human esophageal pathologicalchanges.It is believed to be an ideal animal model to study the development and prevention of esophageal adenocarcinoma in humans. 2. It has been proved that duodenal juice reflux can induce Barrett's esophagus and esophageal adenocarcinoma, and gastric acid reflux can significantly enhance this process and the risk of esophageal adenocarcinoma induced by duodenal juice reflux. 3. The results showed that excessive nitric oxide produced by iNOS is involved in the carcinogenesis of esophageal adenocarcinoma induced by reflux.