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Volume 134, Issue 1, Pages 145-155 (January 2008)


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Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition

Andreas Robinson, Simon Keely, Jörn Karhausen, Mark E. Gerich, Glenn T. Furuta§, Sean P. ColganCorresponding Author Informationemail address

Received 7 May 2007; accepted 13 September 2007. published online 28 September 2007.

Refers to article:
Life in the Gut Without Oxygen: Adaptive Mechanisms and Inflammatory Bowel Disease
Anthony T. Blikslager
Gastroenterology
January 2008 (Vol. 134, Issue 1, Pages 346-348)
Full Text | Full-Text PDF (205 KB)

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.

 Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO

 Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tübingen, Germany

§ Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, The Children’s Hospital, Denver, Colorado

Corresponding Author InformationAddress requests for reprints to: Sean P. Colgan, PhD, Mucosal Inflammation Program, BRB Room 702, 4200 East 9th Avenue, Denver, Colorado 80220. fax: (303) 315-1121.

 All authors declare that they have no conflict of interest to disclose.

 Supported by National Institutes of Health grants HL60569, DE016191, and DK50189 and by a grant from the Crohn’s and Colitis Foundation of America.

PII: S0016-5085(07)01743-X

doi:10.1053/j.gastro.2007.09.033


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