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Secretory Phospholipase A2 is Required to Induce Histologic Changes Associated with Gastroesophageal Reflux in a Murine Model

M. J. Weyant, A. Babu, X. Meng, J. Cleveland*, A. Banerjee, D. Fullerton*. University of Colorado Health Sciences Center, Denver, CO,

Secretory Phospholipase A2 is Required to Induce Histologic Changes Associated with Gastroesophageal Reflux in a Murine Model
BACKGROUND: The earliest response of esophageal mucosa to the presence of acid reflux is the development of oxidative damage and inflammation. This process is thought to contribute to the development of metaplasia in esophageal mucosa known as Barrett’s esophagus as well as the progression to malignancy. Secretory phospholipase A2 (sPLA2) is a mediator of inflammation whose levels are increased in human tissue samples of Barrett’s metaplasia and carcinoma compared to normal mucosa. Our goal is to determine the role of sPLA2 in the development of reflux-associated histoligic changes in esophageal mucosa using strains of mice known to be deficient in sPLA2.
METHODS: sPLA2 deficient (-/-) mice (C57/Bl6 n=5) and mice known to express high (+/+) levels of sPLA2 (BALBc n=2) underwent a side-to-side surgical anastomosis between the first portion of the duodenum and the GE junction allowing mixed exposure of esophageal mucosa to both duodenal and stomach contents. Control animals underwent a laparotomy with incision and repair of the gastroesophageal junction. Recovered animals were then fed a regular diet and euthanized at 4 weeks post procedure. Segments of tissue in graded distances from the GE junction were frozen in embedding medium by immersing in dry ice cooled isopentane. Immunoflourescent staining was performed to confirm the presence or absence of sPLA2 in esophageal tissue. H&E staining was used to identify histologic changes associated with reflux.
RESULTS: Immunofluorescence analysis confirmed the absence of sPLA2 in C57Bl/6 (-/-) and presence in Balb/c (+/+) mice. Hematoxylin and eosin staining demonstrated thickening of the esophageal mucosa in response to gastroesophageal reflux in the presence of sPLA2, however mice lacking sPLA2 were immune to the early histologic changes induced by mixed reflux (Fig.1).
CONCLUSIONS: The presence of sPLA2 appears necessary for early histologic changes induced by exposure of the esophagus to gastroduodenal contents. Further study will be aimed at (1) determining the effect of sPLA2 inhibitors on the development of reflux-associated mucosal histologic changes and (2) studying the role of sPLA2 in the development of esophageal malignancy
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