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Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis

Department of Gastroenterology, Osaka City University, Graduate School of Medicine, Osaka, Japan

Correspondence to:
Correspondence to:
Dr Y Fujiwara
Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi Abenoku, Osaka 545-8585, Japan; yasu{at}med.osaka-cu.ac.jp

ABSTRACT
Background: Although prostaglandin E₂ (PGE₂), cyclooxygenase 2 (COX-2), and microsomal prostaglandin E synthase 1 (mPGES-1) are known to play a role in various inflammatory events, their roles in the pathogenesis of gastro-oesophageal reflux disease are not known.

Aims: We examined the dynamics of COX-1, COX-2, mPGES-1, mPGES-2, cytosolic PGES (cPGES), and PGE₂ synthetic activity in rat acid reflux oesophagitis and the effects of COX-2 inhibitors on the severity of oesophagitis.

Methods: Acid reflux oesophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus. Rats were killed on day 3 (acute phase) or day 21 (chronic phase) after induction of oesophagitis.

Results: Expression of COX-2 and mPGES-1 was markedly increased in oesophagitis while modest changes in COX-1, cPGES, and mPGES-2 expression were observed. COX-2 and mPGES-1 were colocalised in epithelial cells of the basal layer, as well as inflammatory and mesenchymal cells in the lamina propria and submucosa. COX-2 inhibitors significantly reduced the severity of chronic oesophagitis but did not affect acute oesophageal lesions. COX-2 inhibitors significantly inhibited the increase in PGE₂ synthesis in oesophageal lesions on both days 3 and 21. Epithelial proliferation was significantly increased in the basal layer on day 21. Inflammatory cells and epithelial cells of the basal layer exhibited reactions for EP4 in oesophagitis.

Conclusion: PGE₂ derived from COX-2 and mPGES-1 plays a significant role in the pathogenesis of chronic acid reflux oesophagitis, and possibly in basal hyperplasia and persistent inflammatory cell infiltration.

Abbreviations: PG, prostaglandin; COX, cyclooxygenase; mPGES, microsomal prostaglandin E synthase; cPGES, cytosolic prostaglandin E synthase; GORD, gastro-oesophageal reflux disease; PCNA, proliferating cell nuclear antigen; RT-PCR, reverse transcription-polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL-1ß, interleukin 1ß; TNF-, tumour necrosis factor

Keywords: cyclooxygenase 2; microsomal prostaglandin E synthesis 1; prostaglandin E2; cyclooxygenase 2 inhibitors; reflux oesophagitis

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