Article Text

other Versions

PDF
Original article
Hypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD
  1. Xiaofang Huo1,2,
  2. Agoston T Agoston3,
  3. Kerry B Dunbar1,2,
  4. Daisha J Cipher4,
  5. Xi Zhang1,2,
  6. Chunhua Yu1,2,
  7. Edaire Cheng1,5,
  8. Qiuyang Zhang1,2,
  9. Thai H Pham1,6,
  10. Uttam K Tambar7,
  11. Richard K Bruick7,
  12. David H Wang1,2,8,
  13. Robert D Odze3,
  14. Stuart J Spechler1,2,8,
  15. Rhonda F Souza1,2,8
  1. 1Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
  2. 2Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
  3. 3Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  4. 4College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, Texas, USA
  5. 5Department of Pediatrics, Children's Medical Center and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
  6. 6Department of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
  7. 7Department of Biochemistry, University of Texas Southwestern Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  8. 8Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  1. Correspondence to Dr Rhonda F Souza, Department of Gastroenterology, MC# 111B1, Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA; rhonda.souza{at}verizon.net

Abstract

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.

  • OESOPHAGEAL DISEASE
  • INFLAMMATORY DISEASES
  • CELL SIGNALLING
  • CYTOKINES

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.