Expression and significance of inducible nitric oxide synthase in formation of Barrett¬ðs esophagus and its progression to esophageal adenocarcinoma in a rat model

    ZHANG Tao1, ZHU Yiª²Fang1, ZHANG Feng2, WANG Yunª²jie1, CHENG Qingª²Shu1, LI Xiaoª²Fei1

    1Department of Thoracic Surgery, Tangdu Hospital,Xi¬ðan 710038,China£¬2Department of Pharmacology, School of Basic Medicine£¬Fourth Military Medical University, Xi¬ðan 710033,China

    ¡¾Abstract¡¿ AIM: To investigate the expression and significance of inducible nitric oxide synthase (iNOS) in the formation of Barrett¬ðs esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) in a rat model. METHODS: Sixtyª²five eightª²weekª²old male Spragueª²Dawley rats underwent endª²toª²side gastrojejunostomy, followed by endª²toª²side esophagojejunostomy approximately 0ª±5 cm distal to the gastroª²jejunostoma to produce the duodenogastroesophageal reflux model group. Another 10 rats undergoing a sham operative procedure were taken as a control group. Some animals were sacrificed and their esophageal samples were taken from the model group at week 1, 4, 8, 12, 16 and 20 respectively after surgery and from the control group at week 20. Longitudinally esophageal paraffin slides were made and used for hematoxylin and eosin staining and iNOS immunohistochemical staining. Pathological changes and expression of iNOS in the distal oneª²third of the esophageal mucosa were detected microscopically. RESULTS: ¢Ù No pathological changes were found in the control group. Significant esophagitis were observed in the model group after surgery. There was a progression in epithelial cell proliferation and inflammation from mild to severe in the distal oneª²third of the esophagus, and BE and EAC were observed. The incidence of BE and EAC increased with time: 37ª±5% and 0% at week 8, 60% and 10% at week 12, 90% and 30% at week 16, 86.6% and 53ª±3% at week 20. ¢Ú Immunohistochemical staining of iNOS was negative in the control group. In the model group positive expression of iNOS in the distal oneª²third of the esophagus was observed in 0%, 0%, 50%, 80%, 100% and 100% of the rats at week 1, 4, 8, 12, 16 and 20 respectively and in 100% of the rats with BE and EAC. Positive iNOS staining was observed in the stromal macrophages directly beneath the epithelium. CONCLUSION: Excessive nitric oxide produced by iNOS in the stromal macrophages may contribute to the pathogenesis of BE and its progression to EAC. ......