Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition.
OBJECTIVE
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
Andreas
A
Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO, USA.
Keely
Simon
S
Karhausen
Jörn
J
Gerich
Mark E
ME
Furuta
Glenn T
GT
Colgan
Sean P
SP
D000818:Animals; D018929:Cell Culture Techniques; D003092:Colitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D011393:Procollagen-Proline Dioxygenase