Cited by 655Inflammatory Bowel DiseaseGut microbiota and healthDigestive system and related health

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Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis

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Karhausen, Jörn, Furuta, Glenn T., Tomaszewski, John E., Johnson, Randall S., Colgan, Sean P., Haase, Volker H.·2004·Journal of Clinical Investigation

DOI 10.1172/jci200421086PMC PMC522241

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Abstract

Mucosal epithelial cells are uniquely equipped to maintain barrier function even under adverse conditions. Previous studies have implicated hypoxia in mucosal tissue damage resulting from both acute and chronic inflammation. Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a barrier-protective element during mucosal inflammation. Initial studies of hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant HIF-1 activation during colitis. To study this in more detail, we generated 2 mouse lines with intestinal epithelium–targeted expression of either mutant Hif1a (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters. Furthermore, colons with constitutive activation of HIF displayed increased expression levels of HIF-1–regulated barrier-protective genes (multidrug resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss of barrier during colitis in vivo. Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.

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Authors: Karhausen, J., Furuta, G. T., Tomaszewski, J. E., Johnson, R. S., Colgan, S. P., & Haase, V. H.
Affiliations: Brigham and Women's Hospital (US)
University of Pennsylvania (US)
University of California San Diego (US)
ORCID: Karhausen, Jörn
Furuta, Glenn T.
Tomaszewski, John E.
Johnson, Randall S.
Colgan, Sean P.
Haase, Volker H.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2004-10-15
Volume: 114
Issue: 8
Pages: 1098-1106
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci200421086
PMC: PMC522241
OpenAlex: W1982920345
Cited by: 655
References: 60
Citations by year: 2026: 19 · 2025: 25 · 2024: 25 · 2023: 43 · 2022: 29 · 2021: 35 · 2020: 41 · 2019: 37 · 2018: 32 · 2017: 38 · 2016: 46 · 2015: 40 · 2014: 29 · 2013: 44 · 2012: 37
FWCI: 7.83
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Crohn's and Colitis Foundation of America
Massachusetts Institute of Technology
Crohn's and Colitis Foundation
National Institutes of Health (DE13499, DK-50189, PO1 DE13499)
National Heart, Lung, and Blood Institute (R01HL060569, HL-60569)
National Institute of Diabetes and Digestive and Kidney Diseases (K08DK002668, DK02668, R01DK050189, DK062060, R03DK062060, R37DK050189, R29DK050189, DK-50189)
National Institute of Dental and Craniofacial Research (P01 DE 13499, P01DE013499)
Topics: Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Gastroenterology › Digestive system and related health
Keywords: HIF-1, colitis, intestinal epithelium, mucosal barrier, intestinal hypoxia, inflammatory bowel disease, VHL, HIF1A, intestinal epithelial cells, TFF3, CD73, multidrug resistance gene 1, epithelial protection
MeSH terms: Animals, Carrier Proteins, Colitis, DNA-Binding Proteins, Gene Expression Regulation, Humans, Intestinal Mucosa, Mice, Inbred Strains, Mice, Transgenic, Nuclear Proteins, Recombination, Genetic, Transcription Factors, Cell Hypoxia, Gene Deletion, Genes, Reporter, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis

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