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2016 ; 34
(5
): 483-90
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From Reflux Esophagitis to Esophageal Adenocarcinoma
#MMPMID27331918
Souza RF
Dig Dis
2016[]; 34
(5
): 483-90
PMID27331918
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Reflux esophagitis causes Barrett's metaplasia, an abnormal esophageal mucosa
predisposed to adenocarcinoma. Medical therapy for reflux esophagitis focuses on
decreasing gastric acid production with proton pump inhibitors. We have reported
that reflux esophagitis in a rat model develops from a cytokine-mediated
inflammatory injury, not from a caustic chemical (acid) injury. In this model,
refluxed acid and bile stimulate the release of inflammatory cytokines from
esophageal squamous cells, recruiting lymphocytes first to the submucosa and
later to the luminal surface. Emerging studies on acute reflux esophagitis in
humans support this new concept, suggesting that reflux-induced cytokine release
may be a future target for medical therapies. Sometimes, reflux esophagitis heals
with Barrett's metaplasia, a process facilitated by reflux-related nitric oxide
(NO) production and Sonic Hedgehog (Hh) secretion by squamous cells. We have
shown that NO reduces expression of genes that promote a squamous cell phenotype,
while Hh signaling induces genes that mediate the development of the columnar
cell phenotypes of Barrett's metaplasia. Agents targeting esophageal NO
production or Hh signaling conceivably could prevent the development of Barrett's
esophagus. Persistent reflux promotes cancer in Barrett's metaplasia. We have
reported that acid and bile salts induce DNA damage in Barrett's cells. Bile
salts also cause NF-x03BA;B activation in Barrett's cells, enabling them to
resist apoptosis in the setting of DNA damage and likely contributing to
carcinogenesis. Oral treatment with ursodeoxycholic acid prevents the esophageal
DNA damage and NF-x03BA;B activation induced by toxic bile acids. Altering bile
acid composition might be another approach to cancer prevention.
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