Effect Of Cyclooxygenase-2 On The Development Of Barrett's Esophagus And Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EA) is a severe disease with high mortality rate. Almost all EA come from Barrett's esophagus (BE), and the risk of BE's developing to EA is associated with the grade of dysplasia of esophageal epithelium. The incidences of EA and BE have been huge increases over the past several decades. But etiology and pathogenesis of BE and EA remain unclear.Cyclooxygenase-2 (COX-2) can induce cell proliferation. Many studies have indicated that the overexpression of cyclooxygenase-2 is correlative with the development of gastrointestinal tumor, such as gastric or colonic cancer. And some studies showed esophageal tumour, most of which are esophageal squamous carcinoma, may be relative to overexpression of COX-2. But the association between overexpression of COX-2 and esophageal adenocarcinoma and Barrett's esophagus is unknown. In the present paper the histological changes of esophagus, COX-2 expression of esophageal mucosa were studied by animal BE and EA model, and selective COX-2 inhibitor were used so as to investigate the pathogenesis of BE and EA. 1. Establishing a kind of new and safe animal model of BE and EAThe aim of this part is to establish a new and safe animal model of BE and EA. Method: 150 Sprague-Dawley rats were randomized into 4 groups, including control(nonreflux) group, iron(Fe) group, reflux group and reflux adding iron group. Esophagoduodenostomy was operated in the last two groups and sham operation in the former two groups. After 2 weeks, Iron Dextran were injected intraperitoneum of the rats in Fe group and reflux adding iron group (50mg/kg, twice per week for 22 weeks). 5 rats of each group were sacrificed at 8 week after operation and others at 24 week, and esophageal samples were taken. All esophagi were assessed for presence of cancer, BE, and dysplasia by gross and microscopy observation. Results: At 8 week after operation, mucosal coarse was seen and epithelial hyperplasia was found by microscopy. There were severe injuries in esophagus of Fe group and reflux adding iron group. At 24 week, injuries were more severe. The incidence of BE , dysplasia and EA of reflux adding iron group were 57.1% , 31.4% and 20%, compared with those of refulx group were 28.9%, 7.9% and 2.6%(P<0.05). Them were significantly more than those of the other two groups (P<0.05). Conclusion: Iron Dextran can increase the injury of gastroduodenalesophageal reflux to esophageal mucosa and induce the developement of BE and esophageal adenocarcinomain. This model is safe and successful. 2. Association between COX-2 expression and the development of BE and EAThe aim of this part is study the effect of COX-2 and its selective inhibitors on Barrett's esophagus and esophageal adenocarcinoma. Methods: Esophagoduodenostomy were taken in 45 SD rats and then iron Dextran were injected intraperitoneum (50mg/kg, twice per week for 22 weeks). At the same time, Celecoxib (20mg/Kg.d) was given to rats in this group (Celecoxib group). Esophageal samples were taken at 8 week and 24 week and were studied by gross and microscopy observation like other groups. COX-2 epression was examined in all groups by immunohistochemical staining of S-P. Results: The incidence of BE , dysplasia and EA of Celecoxib group(22.2%, 13.8% and 5.6%) were significantly lessthan those of reflux adding iron group (P<0.05), but similar with reflux group. The levels of COX-2 expression in reflux adding iron group, reflux group and Celecoxib group were significantly greater than those in control group and Fe group, and that in Celecoxib group was significantly less than that in reflux adding iron group (P<0.05). The expressions were the strongest in and EA. Conclusion: Increasing express of COX-2 may be associated with the development of BE and EA. By inhibiting the activity of COX-2, selective COX-2 inhibitors could decrease the incidence of BE and esophageal adenocarcinoma. This provides evidence that selective COX-2 inhibitors may have preventive potential in BE and EA.In short, the present study suggests that after long esophageal reflux, iron can induce the developement of BE and EA. COX-2 level is higher in Barrett's esophagus and esophageal adenocarcinoma. Selective COX-2 inhibitors may reduce the activeness of COX-2, decrease the esophageal epithelial cell proliferation and the incidence of esophageal adenocarcinoma.