Exogenous luminal nitric oxide exposure accelerates columnar transformation of rat esophagus

Hiroyuki Endo, Katsunori Iijima, Kiyotaka Asanuma, Nobuyuki Ara, Hirotaka Ito, Naoki Asano, Kaname Uno, Tomoyuki Koike, Akira Imatani, Tooru Shimosegawa

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Exposure of the esophageal mucosa to refluxed gastroduodenal contents is recognized to be an important risk factor for Barrett's esophagus (BE). At the human gastroesophageal junction, nitric oxide is generated luminally through the enterosalivary recirculation of dietary nitrate, and in cases with gastroesophageal reflux, the site of luminal nitric oxide generation could shift to the distal esophagus. The aim of this study is to investigate whether exogenous luminal nitric oxide could promote the development of BE in rats. Sodium nitrite plus ascorbic acid were administered to a rat surgical model of BE, in which the gastroduodenal contents were refluxed into the esophagus to generate exogenous luminal nitric oxide in the esophagus by the acid-catalyzed chemical reaction between the 2 reagents. The emergence of BE was evaluated histologically in the early phase (several weeks) after the surgery with or without exogenous nitric oxide administration. To elucidate the histogenesis of BE, CDX2, MUC2 and MUC6 expressions were investigated immunohistochemically. Coadministration of sodium nitrite plus ascorbic acid significantly accelerated the timing of emergence and increased the area of BE compared with controls. Administration of either reagent alone did not show any promotive effects on BE formation. Immunohistochemically, the columnar epithelium thus induced was similar to the specialized intestinal metaplasia in human BE. The results of this animal model study suggest that exogenous luminal nitric oxide could be involved in the pathogenesis of the columnar transformation of the esophagus. Further studies in human are warranted.

Original languageEnglish
Pages (from-to)2009-2019
Number of pages11
JournalInternational Journal of Cancer
Issue number9
Publication statusPublished - 2010 Nov 1


  • Barrett's esophagus
  • CDX2
  • animal model
  • dietary nitrate
  • nitric oxide


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