Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition
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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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HIF activators limit inflammation in models of inflammatory bowel disease and LPS-induced shock.
“and to limit inflammation in models of inflammatory bowel disease and LPS-induced shock [117–120].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [118]
In these mouse models, the drugs were well tolerated with no significant adverse side effects.
“In these mouse models, the drugs were well tolerated with no significant adverse side effects.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [26]
This problem was rectified by lowering the dose and decreasing the interval of dosing.
“This problem was rectified by lowering the dose and decreasing the interval of dosing26.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [26]
Both DMOG and FG-4497 provide an overall beneficial influence on multiple parameters studied in chemically induced (TNBS or DSS) mouse models of colitis.
“Indeed, these studies have shown that both DMOG and FG-4497 provide an overall beneficial influence on multiple parameters studied in chemically induced (trinitrobenzene sulfonic acid [TNBS] or dextran sodium sulfate [DSS] mouse models of colitis.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [26]
Within the gastrointestinal tract, the PHD inhibitors DMOG and FG-4497 have been used effectively to reduce symptoms in at least two mouse models of colitis.
“Within the gastrointestinal tract, the PHD inhibitors DMOG and FG-4497 have been used effectively to reduce symptoms in at least two mouse models of colitis23,26.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [26]
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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.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 134
- Issue
- 1
- Pages
- 145-155
- ISSN
- 0016-5085 (ISSN-L)
- 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
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Epidemiology › 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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