Cited by 369Inflammatory Bowel DiseaseCancer, Hypoxia, and MetabolismMicroscopic Colitis

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Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition

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Robinson, Andreas, Keely, Simon, Karhausen, Jörn, Gerich, Mark E., Furuta, Glenn T., Colgan, Sean P.·2008·Gastroenterology

DOI 10.1053/j.gastro.2007.09.033PMC PMC2194638

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Abstract

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.

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Authors: Robinson, A., Keely, S., Karhausen, J., Gerich, M. E., Furuta, G. T., & Colgan, S. P.
Affiliations: University of Colorado Health (US)
Universitätsklinikum Tübingen (DE)
Corresponding author: Colgan, Sean P.
ORCID: Keely, Simon
Karhausen, Jörn
Gerich, Mark E.
Furuta, Glenn T.
Colgan, Sean P.
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2008-01
Volume: 134
Issue: 1
Pages: 145-155
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2007.09.033
PMC: PMC2194638
OpenAlex: W2133938746
Cited by: 368
References: 46
Citations by year: 2026: 13 · 2025: 6 · 2024: 12 · 2023: 14 · 2022: 11 · 2021: 18 · 2020: 21 · 2019: 15 · 2018: 17 · 2017: 21 · 2016: 36 · 2015: 28 · 2014: 25 · 2013: 30 · 2012: 27
FWCI: 9.68
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Gastroenterology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Crohn's and Colitis Foundation of America
National Institutes of Health
National Heart, Lung, and Blood Institute (R01HL060569, HL-60569)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050189, R37DK050189, R29DK050189, T32DK007038, DK-50189)
National Institute of Dental and Craniofacial Research (P50DE016191, P01DE013499, DE 016191)
Topics: Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Gastroenterology › Microscopic Colitis
Keywords: hypoxia-inducible factor-1α, prolyl hydroxylase inhibition, tissue hypoxia, mucosal protection, inflammatory bowel disease, TNBS-induced colitis, erythropoietin, TNF-α, barrier function, wound healing, colitis
MeSH terms: Animals, Colitis, Disease Models, Animal, Enzyme Inhibitors, HeLa Cells, Humans, Intestinal Mucosa, Male, Procollagen-Proline Dioxygenase, Cell Culture Techniques, Mice, Hypoxia-Inducible Factor 1

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Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition

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