Gastric carditis: Is it a histological response to high concentrations of luminal nitric oxide?

Abstract

During the last decade, inflammation (carditis) and intestinal metaplasia localized to immediately below the human gastro-oesophageal junction have received much attention in relation to the rising incidence of cancer at this site. Since these histological findings are frequently observed even among those who are H pylori-negative, the causative factors for such histologic events at the human gastro-oesophageal junction remain obscure. A series of recent studies have demonstrated that a high level of salivary nitrite is sustained over several hours after the ingestion of a high nitrate meal, and that the nitrite in swallowed saliva is rapidly converted to nitric oxide by an acid catalyzed chemical reaction at the gastro-oesophageal junction. Eventually, a substantial amount of nitric oxide diffuses from the lumen into the adjacent tissue. Therefore, the human gastro-oesophageal junction is likely to be a region of high nitrosative stress. Considering the life-time exposure of the gastro-oesophageal junction to cytotoxic levels of nitric oxide, this may account for the high prevalence of inflammation, intestinal metaplasia, and subsequent development of neoplasia at this site. Although gastric acid, pepsin, and bile acid have been intensively investigated as a cause of adenocarcinoma at the gastro-oesophageal junction and the distal esophagus, nitric oxide and the related nitrosative stress should also be examined.

Figure 1

Nitric oxide chemistry at human gastro-oesophageal junction. Nitrite (NO₂^-) in swallowed saliva is converted to nitric oxide (NO) promptly at the gastro-oesophageal (GO) junction where encountering gastric acid containing ascorbic acid. NO thus formed diffuses into the adjacent tissue of the GO junction because of its gaseous and lipophilic properties. The majority of the NO arising from the lumen will be exhausted within the superficial mucosal layer by reacting with surrounding molecules while a small portion of the NO can reach the inner muscular layer. The luminal generation of NO is sustained for several hours after nitrate ingestion, during which period the GO junction is exposed to abundant amounts of NO.