Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition

A Robinson, S Keely, J Karhausen, ME Gerich… - Gastroenterology, 2008 - Elsevier
A Robinson, S Keely, J Karhausen, ME Gerich, GT Furuta, SP Colgan
Gastroenterology, 2008Elsevier
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
involving epithelial cells. In this context, a protective role for the transcriptional regulator
hypoxia-inducible factor (HIF) was shown through conditional deletion of epithelial HIF-1α 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 …
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 involving epithelial cells. In this context, a protective role for the transcriptional regulator hypoxia-inducible factor (HIF) was shown through conditional deletion of epithelial HIF-1α 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-1α and subsequently drives the expression downstream of HIF target genes (eg, erythropoietin).
RESULTS
Our results show that the FG-4497–mediated induction of HIF-1α provides an overall beneficial influence on clinical symptoms [weight loss, colon length, tissue tumor necrosis factor-α (TNFα)] 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-1α during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.
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