title: From Reflux Esophagitis to Esophageal Adenocarcinoma.
abstract: 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.
authors.affiliation: Esophageal Diseases Center, Department of Medicine, VA North Texas Health Care System, Dallas, Tex., USA.
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology*; D000818:Animals; D001471:Barrett Esophagus / Q000473:pathology*; D001647:Bile Acids and Salts / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000209:etiology*; D004947:Esophagus / Q000473:pathology*; D005744:Gastric Acid / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000150:complications* / Q000188:drug therapy; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D054328:Proton Pump Inhibitors; D051381:Rats; D015398:Signal Transduction; D014580:Ursodeoxycholic Acid
chemical_list: D001647:Bile Acids and Salts; D016207:Cytokines; D053823:Hedgehog Proteins; D054328:Proton Pump Inhibitors; D009569:Nitric Oxide; D014580:Ursodeoxycholic Acid