Oxidative stress is more important than acid in the pathogenesis of reflux oesophagitis in rats.

Abstract

Although antisecretory medications such as histamine type II receptor antagonists or proton pump inhibitors have been used to treat reflux oesophagitis, a considerable number of patients do not achieve complete mucosal healing or suffer from either sustained symptoms or ensuing complications, suggesting other damaging factors or impaired mucosal resistance are also involved in the pathogenesis of reflux oesophagitis. The present study was designed to evaluate oxidative stress as the major pathogenic factor of reflux oesophagitis and to determine the usefulness of antioxidants in the treatment of reflux oesophagitis. Reflux oesophagitis was induced by insertion of a 3 mm calibre ring into the duodenum, 1 cm distal to the ligament of Treitz, in Sprague-Dawley rats. DA-9601, a novel antioxidant substance, significantly attenuated the gross and histopathological scores of reflux oesophagitis compared with those treated with ranitidine alone or reflux oesophagitis controls in a dose dependent manner. Only scattered erosions were observed in the antioxidant pretreated group but acid suppression by ranitidine was not effective in decreasing the severity of reflux oesophagitis. Significantly increased amounts of malondialdehyde (MDA), increased nuclear factor kappaB (NFkappaB) activation, and depletion of reduced glutathione (GSH) were observed in experimentally induced reflux oesophagitis. DA-9601 pretreatment attenuated the decrement in mucosal GSH levels and decreased MDA formation significantly. DA-9601 treatment caused significant reductions in activation of NFkappaB transcription factor, especially the p50 subunit, in accordance with the significantly higher levels of inhibitory protein of NFkappaB expression. Reflux oesophagitis caused considerable levels of oxidative stress in the oesophageal mucosa and antioxidant treatment should be considered as supplementary therapy in the prevention or treatment of reflux oesophagitis with acid suppression.