Reactive nitrogen oxide species induce dilatation of the intercellular space of rat esophagus

Abstract

Objective. Dilatation of the intercellular space (DIS) of the esophageal epithelium is recognized as one of the earliest histological changes in gastroesophageal reflux disease patients. At the human gastroesophageal junction, reactive nitrogen oxide species (RNOS) are generated luminally through the entero-salivary re-circulation of dietary nitrate. In cases with gastroesophageal reflux, the site of luminal RNOS generation may shift to the distal esophagus. The aim of this study was to investigate whether luminal RNOS exposure could be involved in the pathogenesis of DIS. Material and methods. Rat esophageal mucosa was studied with an Ussing chamber model. On the luminal side of the chamber, RNOS were generated by the acidification of physiologic concentrations of sodium nitrite (1.0 or 5.0 mM). Esophageal barrier function was assessed by means of electrophysiological transmembrane resistance and membrane permeability by means of ³H-mannitol flux. The dimensions of the intercellular spaces were assessed by using transmission electron microscopy. Results. Administration of acid plus sodium nitrite induced DIS of the esophageal epithelium, and this ultrastructural morphological change was accompanied by a concomitant decrease in the transmembrane resistance and an increase in the epithelial permeability. The DIS induced by luminal RNOS was also confirmed in an in vivo exposure model. Conclusions. The present animal study indicates that the RNOS generated by the acidification of salivary nitrite in the presence of refluxed gastric acid in the esophagus could be a luminal factor that is responsible for the induction of DIS. Further studies are warranted to investigate the clinical relevance of the present findings to the human situation.

Key Words::

• Dilatation of intercellular space
• gastroesophageal reflux disease
• nitric oxide
• reactive nitrogen oxide species
• transmission electron microscopy

Acknowledgement

This work was supported in part by Grants-in-Aid to K. I. (19590710) and K. A. (20790484) from the Ministry of Education, Science, Sports and Culture in Japan. The authors report no conflicts of interest.