Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis
Jörn Karhausen, … , Sean P. Colgan, Volker H. Haase
Jörn Karhausen, … , Sean P. Colgan, Volker H. Haase
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1098-1106. https://doi.org/10.1172/JCI21086.
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Article Cell biology

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

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.

Authors

Jörn Karhausen, Glenn T. Furuta, John E. Tomaszewski, Randall S. Johnson, Sean P. Colgan, Volker H. Haase

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Impairment of barrier function through conditional deletion of Hif1a in ...
Impairment of barrier function through conditional deletion of Hif1a in intestinal epithelium. (A) Lack of HIF-1 induction in conditional Hif1a mutants in whole-body hypoxia. Western blot analysis of nuclear HIF-1α levels from colonic scrapings of WT littermates or conditional Hif1a mice subjected to normoxia (Nx; 21% O2, 4 h) or hypoxia (Hx; 8% O2, 4 h). (B) Mucosal colonic scrapings 7 days after induction of TNBS colitis compared with vehicle control. HIF-1α levels in Hif1a mutants failed to respond, which indicates successful impairment of the HIF-1 pathway. (C) Ex vivo assay of barrier electrical resistance in colonic tissue explants. In samples derived from WT animals (filled squares), resistance increased in hypoxia (*P – 0.05 after 3–6 h). In contrast, both in hypoxic samples from Hif1a conditional mutant animals (filled circles) and in all normoxic samples (WT, open squares; Hif1a mutant, open circles), measurements gradually dropped. (D) Changes of body weight following induction of TNBS colitis. When compared with their WT littermates (filled squares, n = 14), Hif1a conditional mutant mice (filled circles, n = 25) displayed a more severe clinical course with significantly greater and ongoing loss of weight (P < 0.01 by ANOVA). No difference between vehicle control–treated Hif1a mutant and WT animals was observed (open squares). (E) Colon length relative to vehicle control–treated (ETOH) littermates 7 days after induction of colitis. Hif1a conditional mutant animals displayed significant shortening of the colon ( P – 0.05 vs. TNBS-treated WT, *P – 0.05 vs. vehicle-treated controls).