Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition.
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.
Robinson, A; Keely, S; Karhausen, J; Gerich, ME; Furuta, GT; Colgan, SP
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