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

Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH
J Clin Invest. 2004 114 (8): 1098-106

PMID: 15489957 · PMCID: PMC522241 · DOI:10.1172/JCI21086

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.

MeSH Terms (18)

Animals Carrier Proteins Cell Hypoxia Colitis DNA-Binding Proteins Gene Deletion Gene Expression Regulation Genes, Reporter Humans Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Intestinal Mucosa Mice Mice, Inbred Strains Mice, Transgenic Nuclear Proteins Recombination, Genetic Transcription Factors

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