Barrett's esophagus (BE) is a premalignant disease associated with esophageal adenocarcinoma (EAC). This condition is highly associated with gastroesophageal reflux disease (GERD) which is characterized as chronic exposure of the esophagus to acid and bile acids. An understanding of the cytotoxic and tumorigenic capacity of bile acids and acid during a reflux episode will lead to the identification of markers for therapeutic intervention. The major goal of the following studies was to determine the mechanisms responsible for bile acid-induced alteration in intracellular pH (pHi) the effect on DNA damage, apoptosis and the adaptive resistance to reflux episodes in cells derived from normal esophagus (HET1A) or BE (CP-A) and EAC (JH-EsoAd1). In addition, I explored the therapeutic potential of UDCA oral therapy in BE cells.Here we show a novel mechanism of bile acid-induced, nitric oxide-mediated inhibition of the sodium-hydrogen exchanger (NHE) is a pathway bile acids utilize to induce acid-mediated DNA damage. This same mechanism can elicit apoptosis-resistance which we demonstrate by the complete inhibition of NHE with pharmacological inhibitor of NHE, EIPA. In addition, chronic exposure of bile acids and acid, in-vitro, confers resistance to cytotoxicity and makes cells derived from the squamous epithelium of the esophagus resemble BE and EAC. Finally, modifying the bile acid composition with glycol-Ursodeoxycholic acid (GUDCA) prevents many of the malignant effects of bile acids and acid and suggests a possible therapeutic strategy for those that suffer from GERD. The conclusion from this study suggest that bile acid reflux should be controlled in patients who suffer from GERD
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/195890 |
| Date | January 2010 |
| Creators | Goldman, Aaron |
| Contributors | Dvorak, Katerina, Dvorak, Katerina, Gerner, Eugene, Delamere, Nicholas, Zhang, Donna, Wondrak, Georg, Bernstein, Harris |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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