TY - JOUR
T1 - A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2α
T2 - a potential role for targeting HIF-2α to prevent and treat reflux esophagitis
AU - Souza, Rhonda F.
AU - Bayeh, Liela
AU - Spechler, Stuart J.
AU - Tambar, Uttam K.
AU - Bruick, Richard K.
N1 - Funding Information:
This work was supported by the National Institutes of Health (R01-DK63621 and R01-DK103598 to R.F.S. and S.J.S.; R01-GM102604 to U.K.T.); W.W. Caruth, Jr. Endowed Scholarship and the Welch Foundation (I-1748 to U.K.T.); Sloan Research Fellowship (U.K.T.); R.K.B. is the Michael L. Rosenberg Scholar in Medical Research and was supported by the Cancer Prevention and Research Institute of Texas (RP130513) and the Welch Foundation (I-1568 to R.K.B.).
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/12
Y1 - 2017/12
N2 - 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.
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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U2 - 10.1016/j.coph.2017.10.004
DO - 10.1016/j.coph.2017.10.004
M3 - Review article
C2 - 29112883
AN - SCOPUS:85032816842
SN - 1471-4892
VL - 37
SP - 93
EP - 99
JO - Current Opinion in Pharmacology
JF - Current Opinion in Pharmacology
ER -