Involvement of luminal nitric oxide in the pathogenesis of the gastroesophageal reflux disease spectrum

Abstract

Over the last 3 decades, the incidence of esophageal adenocarcinoma has dramatically increased in Western countries; a similar increase may be observed in Asian countries in the near future. Esophageal adenocarcinoma arises from a sequential gastroesophageal reflux disease (GERD) spectrum from reflux erosive esophagitis, to Barrett's esophagus, and finally to esophageal adenocarcinoma. At present, gastric acid and bile are assumed to be primarily involved in the etiology of the GERD spectrum. We reported in 2002 that, at the gastroesophageal junction in humans, abundant amounts of nitric oxide (NO) are generated luminally through the entero-salivary re-circulation of dietary nitrate. Since then, we have carried out a series of experiments to demonstrate that NO diffuses into the adjacent epithelium at cytotoxic levels. This diffusion results in disruption of the epithelial barrier function, exacerbation of inflammation, acceleration of columnar transformation in the esophagus (Barrett's esophagus) via the induction of caudal-type homeobox 2, and the shifting of carcinogenic N-nitroso compound formation from the luminal to epithelial compartment. These results suggest that, in addition to conventionally recognized causative factors, luminal NO could also be involved in the pathogenesis of the GERD spectrum. In addition, we recently showed that there is a prominent gender-related difference in NO-related cytotoxicity in the esophagus and that estrogen attenuated the esophageal tissue damage via the estrogen receptor in female rats. The role of estrogen in attenuating the esophageal tissue damage in NO-related esophageal damage could explain the well-recognized male predominance in the GERD spectrum in humans.

Individual and Combined Effects of Environmental Risk Factors for Esophageal Cancer Based on Results From the Golestan Cohort Study

“…possible mechanisms might be through the increased endogenous production of nitrosamines and nitric oxide following ingestion of additional nitrates in water. 50,51 Regarding the association of indoor air pollution and increased ESCC risk, these findings are consistent with the case-control studies conducted in high-incidence regions of Asia, 52 Africa, 12 South America, 12 and Europe. 13 Diesel, kerosene, and biomass are the nongas fuels used for house heating and cooking in Golestan.…”

Modulation of the formation of active forms of nitrogen by ingredients of plant products in the inhibition of carcinogenesis

“…Гастроэзофагеальное рефлюксное заболевание повышает риск развития аденокарциномы пищевода. Есть основания считать, что заболевание связано, в том числе, с повреждениями, вызываемыми цитотоксическими локальными концентрациями NO, образовавшегося при восстановлении НА в слюне, где накапливается до 25 % НА, поступивших с пищей и водой [140]. На модели гастродуоденального рефлюкса с сохраненной функцией желудка введение крысам связывающего НИ тиопролина (производного гетероциклической аминокислоты пролина, тиазолидин-4-карбоксильной кислоты) полностью предотвращало образование аденокарциномы пищевода, в то время как различий в возникновении плоскоклеточной карциномы пищевода в контрольной и опытной группах не было выявлено [141].…”

Some of the effective factors in the pathogenesis of gastro‐oesophageal reflux disease

“…The pro‐inflammatory cytokines cause iNOS expression in many cells. The excessive production of NO as an inflammatory interface can cause tissue destruction in inflammatory autoimmune disease . Depending on the amount of NO concentration, it can act as either a pro‐inflammatory or anti‐inflammatory agent.…”

“…As shown in Figure 1 The excessive production of NO as an inflammatory interface can cause tissue destruction in inflammatory autoimmune disease. 11 Depending on the amount of NO concentration, it can act as either a pro-inflammatory or anti-inflammatory agent. Soluble guanylyl cyclase is the main receptor of NO in the cell membrane.…”