BILE REFLUX INDUCED MUTAGENESIS ON ESOPHAGEAL EPITHELIUM IN AN ANIMAL MODEL AND ITS EFFECT IN CELL SIGNALING Ben Selvan MS, Anu Korula MD, Anoop Ramachandran PhD, Jaya kumar MSc, Sathish Kumar MSc, George MS, Christian Medical College ,Vellore
Background: . Bile reflux has been suggested to have a mutagenic effect on esophageal epithelium. However, signaling events in vivo are not well understood
Aim: Animal models in which Barrett’s esophagus and/or carcinoma can be induced by Bile reflux.To understand signalling events playing a role in the process, the role of p38 & ERK MAP kinases was also examined.
Methods: Thirty Wistar rats[ 150gms]were taken , 60% of the animals were subjected to side to side and 40 % were end to side oesophago-duodenostomy. Hematoxylin and eosin stains were used .To examine signalling events, p38 & ERK MAP kinase activation was determined by immuno-blotting for the phosphorylated active forms of the protein.
Results: Mortality after the procedure was 40 %, which was higher in the end to side group.17 rats survived through one year, of which eight developed nodular lower esophageal mucosa, 0.8×0.5cm. Three rats did not show any changes as the side to side anastamosis had stenosed. 6 had papillomatosis, epithelial hyperplasia and acanthosis and 4 had basal cell hyperplasia,allof them had severe erosive oesophagitis. Contrary to most reports, none of the animals developed either dysplasia or carcinoma. The histopathologic evaluation was more suggestive of a reactive lesion fitting the diagnosis of “esophagitis cystica.” Animals which had undergone biliary diversion showed significant increase in phosphorylation of both p38 & ERK MAP kinase.
Conclusion: End to side oesophago-duodenostomy is the best animal bile reflux model but with high perioperative mortality.The animals in our group only developed “esophagitis cystica” However, signalling events such as MAP kinase phosphorylation, which has been shown to induce cellular proliferation, are induced in our model, since activation of p38 & ERK MAP kinases was evident. This suggests that apart from bile as agent to induce cellular proliferation it is possible that coexistent factors might play a key role in development of carcinoma and the duration of the bile reflux
Program Number: P081