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Introduction: To study the molecular mechanisms underlying how reflux esophagitis causes Barrett's metaplasia, an appropriate animal model is desirable. A number of surgical, rat models of GERD and Barrett's esophagus are available, but genetic engineering of rats is not accomplished readily. In contrast, constitutive and conditional transgenic mice as well as knockout allele mice can be engineered readily and, therefore, mouse models would be highly advantageous for studying the molecular pathogenesis of GERD and Barrett's esophagus. Surgical reflux models in mice have been difficult to establish due to the technical difficulty and high mortality associated with esophageal surgery in such small animals. The limited mouse models that have been described lack adequate molecular characterization to confirm the development of Barrett's metaplasia. We now describe the development and characterization of Barrett's-like columnar metaplasia in mice that have reflux esophagitis induced by esophagojejunostomy (EJ). Methods: To induce reflux, we performed EJ in twenty C57Bl/6 mice weighing 15 to 33 grams. At various time points thereafter, the distal esophagus was removed, paraffin-embedded, sectioned, and mounted on slides, which were stained with H&E and with Alcian blue. Immunohistochemistry was performed to determine expression of Sox-9 (a columnar cell transcription factor expressed in human Barrett's metaplasia) and the columnar cell cytokeratin (CK)18. CK14 (an esophageal squamous cell cytokeratin) was used as a control. We evaluated the specimens for squamous basal cell and papillary hyperplasia typical of reflux esophagitis, as well as for columnar metaplasia. Results: Procedural mortality was 40% for the first 10 animals, but dropped to 20% for the next 10 animals. At 13 weeks after EJ, erosive esophagitis with prominent squamous basal cell and papillary hyperplasia was present in all animals. Columnar metaplasia, with goblet cells that stained with Alcian blue, developed by week 34. The columnar metaplasia expressed CK18, but not CK14. Intense expression of Sox-9 was detected in areas of columnar metaplasia. In the squamous epithelium close to the EJ anastomosis, furthermore, Sox-9 expression was seen in scattered basal cells, whereas squamous epithelium further from the anastomosis did not exhibit Sox-9 expression. Conclusions: EJ can be performed successfully in C57Bl/6 mice, causing reflux esophagitis and, later, goblet cell-containing columnar metaplasia that expresses CK18 and Sox-9. These data suggest that this surgical, mouse model recapitulates the phenotypic and molecular changes seen in human Barrett's esophagus. Thus, we have established a relevant and genetically-modifiable model for studying the molecular pathogenesis of Barrett's esophagus.