Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579307
Title: A new model for studying the effects of NSAIDs on cell migration in the canine gastric epithelium
Author: Hollins, Rachael
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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Abstract:
NSAIDs, which act as COX antagonists, are widely used in veterinary practice to provide long-term pain relief, however a major limiting complication of their use in dogs is gastric ulceration. Gastric ulceration may result from either direct toxic effects on gastric epithelial cells or systemic action, including the inhibition of gastric epithelial cell migration. The role of cell migration in this effect and the specific signalling pathways involved are not known. COX-derived prostaglandins are known to have an important role in gastric defence and cytoprotection through the promotion of gastric mucosal blood flow and mucus secretion and the inhibition of gastric acid secretion. Given the importance of gastric epithelial cell migration in re-establishing gastric mucosal integrity following injury, the aim of this investigation was to test the hypothesis that paracrine PGE2 signalling modulates gastric epithelial cell migration. In order to address this hypothesis, a primary cell culture model which incorporates intact canine gastric glands that spread to form monolayer cell islands, was first characterised and then used. The effects of non-selective and COX-2 selective antagonism on cell spreading in this model and wound healing in immortalised cell monolayers was assessed. Furthermore, the involvement of subtype-specific EP receptor signalling in PGE2-mediated modulation of epithelial cell migration was investigated through treatment with specific agonists and antagonists. Both non-selective and COX-2 selective antagonism inhibited PGE2 production and epithelial cell migration, thus providing evidence that COX-2-derived PGE2 is important for the modulation of epithelial cell migration. Furthermore, non-selective and COX-2 selective antagonism inhibited cellular protrusive activity. The effects of PGE2 on epithelial cell migration were shown to be mediated through EP3 and EP4 receptor signalling. Expression of COX-2, EP3 and EP4 was found to be readily induced in response to stressors. Interestingly, COX-2 expression was up-regulated in patients infected with spiral bacteria. These findings provide evidence that COX-2-derived PGE2 stimulates epithelial cell migration and the formation of cellular protrusions. Thus, reduced PGE2 production in the gastric mucosa may inhibit gastric epithelial migration and contribute to the ulcerogenic effects associated with COX antagonist therapy.
Supervisor: Noble, P.-J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.579307  DOI: Not available
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