Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition

Gastroenterology. 2008 Jan;134(1):145-55. doi: 10.1053/j.gastro.2007.09.033.

Abstract

Background & aims: A number of recent studies have implicated tissue hypoxia in both acute and chronic inflammatory diseases, particularly as they relate to mucosal surfaces lined by epithelial cells. In this context, a protective role for the transcriptional regulator hypoxia-inducible factor (HIF) was shown through conditional deletion of epithelial HIF-1alpha in a murine model of colitis. Here, we hypothesized that pharmacologic activation of HIF would similarly provide a protective adaptation to murine colitic disease.

Methods: For these purposes, we used a novel prolyl hydroxylase (PHD) inhibitor (FG-4497) that readily stabilizes HIF-1alpha and subsequently drives the expression downstream of HIF target genes (eg, erythropoietin).

Results: Our results show that the FG-4497-mediated induction of HIF-1alpha provides an overall beneficial influence on clinical symptoms [weight loss, colon length, tissue tumor necrosis factor-alpha (TNFalpha)] in murine trinitrobenzene sulfonic acid (TNBS) colitis, most likely because of their barrier protective function and wound healing during severe tissue hypoxia at the site of inflammation.

Conclusions: Taken together these findings emphasize the role of epithelial HIF-1alpha during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Colitis / metabolism*
  • Colitis / pathology
  • Colitis / prevention & control
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Hypoxia-Inducible Factor 1
  • Procollagen-Proline Dioxygenase