RT Journal Article
SR Electronic
T1 Hypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1542
OP 1554
DO 10.1136/gutjnl-2016-312595
VO 66
IS 9
A1 Xiaofang Huo
A1 Agoston T Agoston
A1 Kerry B Dunbar
A1 Daisha J Cipher
A1 Xi Zhang
A1 Chunhua Yu
A1 Edaire Cheng
A1 Qiuyang Zhang
A1 Thai H Pham
A1 Uttam K Tambar
A1 Richard K Bruick
A1 David H Wang
A1 Robert D Odze
A1 Stuart J Spechler
A1 Rhonda F Souza
YR 2017
UL http://gut.bmj.com/content/66/9/1542.abstract
AB Objective In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs).Design Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2 weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs. We exposed human oesophageal squamous cell lines to acidic bile salts, and evaluated effects on HIF activation, p65 function, pro-inflammatory molecule production and immune cell migration.Results In patient biopsies, increased immunostaining for HIF-2α and phospho-p65, and increased pro-inflammatory molecule mRNA levels were seen when RO redeveloped 1 or 2 weeks after stopping PPIs. In oesophageal cells, exposure to acidic bile salts increased intracellular reactive oxygen species, which decreased prolyl hydroxylase function and stabilised HIF-2α, causing a p65-dependent increase in pro-inflammatory molecules; conditioned media from these cells increased T cell migration rates. HIF-2α inhibition by small hairpin RNA or selective small molecule antagonist blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts.Conclusions In patients developing RO, increases in oesophageal HIF-2α correlate with increased pro-inflammatory molecule expression. In oesophageal epithelial cells, acidic bile salts stabilise HIF-2α, which mediates expression of pro-inflammatory molecules. HIF-2α appears to have a role in RO pathogenesis.Trial registration number NCT01733810; Results.