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

Rhonda F. Souza, Liela Bayeh, Stuart J. Spechler, Uttam K. Tambar, Richard K. Bruick

Research output: Contribution to journalReview article

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)93-99
Number of pages7
JournalCurrent Opinion in Pharmacology
Volume37
DOIs
StatePublished - Dec 1 2017

Fingerprint

Peptic Esophagitis
Gastroesophageal Reflux
Cytokines
Inflammation
Acids
Wounds and Injuries
Bile Reflux
Caustics
Kidney Neoplasms
Bile Acids and Salts
Esophagus
Protein Isoforms
Epithelial Cells
endothelial PAS domain-containing protein 1
Clinical Trials
T-Lymphocytes

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

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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.",
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AU - Souza, Rhonda F.

AU - Bayeh, Liela

AU - Spechler, Stuart J.

AU - Tambar, Uttam K.

AU - Bruick, Richard K.

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AB - 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.

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