Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Robinson, A; Keely, S; Karhausen, J; Gerich, ME; Furuta, GT; Colgan, SP

Published Date

  • January 2008

Published In

Volume / Issue

  • 134 / 1

Start / End Page

  • 145 - 155

PubMed ID

  • 18166352

Pubmed Central ID

  • 18166352

Electronic International Standard Serial Number (EISSN)

  • 1528-0012

Digital Object Identifier (DOI)

  • 10.1053/j.gastro.2007.09.033

Language

  • eng

Conference Location

  • United States