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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Conditional Vhlh deletion results in constitutive activation of the HIF-...
Conditional Vhlh deletion results in constitutive activation of the HIF-1 pathway in the whole-body hypoxia model. (A and B) Western blot analysis for HIF-1α and HIF-2α in conditional Vhlh mutant animals and WT littermates subjected to normoxia (21% O2, 4 hours) or hypoxia (8% O2, 4 hours). In contrast to WT animals, which display normal regulation, mutant animals constitutively overexpress HIF-1α (A) and HIF-2α (B). (C and D) HIF-1–dependent gene induction is exemplified by induction of ITF on both the transcriptional level (C) and the translational level (D) from colonic tissue derived from control and conditional Vhlh mutant animals subjected to normoxia or hypoxia. (E) Quantitation of serum FITC-dextran as a measure of intestinal permeability in control and conditional Vhlh mutant animals subjected to hypoxia or normoxia. Conditional deletion of Vhlh abrogated the increase in permeability observed in control animals ( P < 0.025 vs. hypoxic WT, *P – 0.05 vs. normoxic controls).