A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2α: a potential role for targeting HIF-2α to prevent and treat reflux esophagitis. (December 2017)

• Record Type: Journal Article
• Authors: Souza, Rhonda F; Bayeh, Liela; Spechler, Stuart J; Tambar, Uttam K; Bruick, Richard K
• Is Part Of: Current opinion in pharmacology. Volume 37(2017)
• Page Start: 93
• Page End: 99
• Publication Date: 2017-12
• Subjects: Pharmacology -- Periodicals; Pharmaceutical Preparations -- Periodicals; Drug Therapy -- Periodicals; Biopharmaceutics -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Periodicals; 615.105
• DOI: 10.1016/j.coph.2017.10.004
• Languages: English
• ISSNs: 1471-4892

Abstract

Highlights: Reflux esophagitis (RE) traditionally was thought to develop as a caustic chemical injury. Recent studies show that RE develops as a cytokine-mediated injury initiated by HIF-2α. Refluxed material stabilizes esophageal HIF-2α, which increases inflammatory cytokine levels. Highly selective HIF-2α small molecule inhibitors have been developed and are in clinical trials. Investigational opportunities are open for HIF-2α-directed therapies in RE. Abstract : Traditionally, reflux esophagitis was assumed to develop as a caustic, chemical injury inflicted by refluxed acid. Recently, however, studies in rats and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury, with hypoxia inducible factor (HIF)-2α playing a major role. In response to the reflux of acid and bile, HIF-2α in esophageal epithelial cells becomes stabilized, thereby increasing production of pro-inflammatory cytokines that attract T lymphocytes and other inflammatory cells to damage the esophagus. Recent studies have identified small molecule inhibitors of HIF-2α that demonstrate exquisite isoform selectivity, and clinical trials for treatment of HIF-2α-driven kidney cancers are ongoing. It is conceivable that a HIF-2α-directed therapy might be a novel approach to prevention and treatment of reflux esophagitis.