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-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.

Abbreviations used in this paper: ANOVA, analysis of variance, ELISA, enzyme-linked immunoabsorbent assay, EPO, erythropoietin, FITC, fluorescein isothiocyanate, HIF-1α, hypoxia-inducible factor 1α, HRE, hypoxia response element, IFNγ, interferon-γ, LPS, lipopolysaccharide, PCR, polymerase chain reaction, PHD, prolyl hydroxylase, TAD, transactivation domain, TNBS, trinitrobenzene sulfonic acid, TNFα, tumor necrosis factor-α, WT, wild-type