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.
View: Text | PDF
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

×

Figure 5

Options: View larger image (or click on image) Download as PowerPoint
Conditional deletion of epithelial Vhlh protects from experimental colit...
Conditional deletion of epithelial Vhlh protects from experimental colitis. (A) Vhlh mutant animals (filled circles, n = 12) recovered their initial weight loss after administration of TNBS significantly faster than WT littermates (filled squares, n = 22; P < 0.01 by ANOVA). Values for vehicle control–treated Vhlh mutant and WT animals were combined (open squares). (B) Colonic length was significantly decreased in WT TNBS-treated animals compared with conditional Vhlh mutant animals with TNBS colitis ( P – 0.05 vs. TNBS-treated WT animals, *P – 0.05 vs. vehicle-treated controls). (C) Real-time PCR analysis for GLUT-1, ITF, MDR1, and CD73. Data are presented as fold ± SEM increase over vehicle control–treated WT animals (represented by the line at 1-fold increase). While TNBS treatment significantly induced all 4 genes (*P – 0.05 vs. vehicle-treated WT), such differences were enhanced in conditional Vhlh mutant animals exposed to TNBS in regard to ITF, MDR1, and CD73 ( P – 0.05 vs. TNBS-treated WT, –P – 0.05 vs. vehicle-treated Vhlh mutants). (D) Significantly lower flux of the FITC-dextran as a measure of intestinal permeability in TNBS-treated Vhlh mutant compared with TNBS-treated WT animals ( P – 0.05; P not significant for TNBS-treated Vhlh mutants vs. vehicle control–treated mice). As no difference was seen between mutant and WT vehicle control–treated animals (compare with Figure 4E), values were combined.