Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function

Files in This Item:
File Description SizeFormat 
Paper201.pdf677.67 kBAdobe PDFDownload
Title: Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function
Authors: Tambuwala, Murtaza M.
Cummins, Eoin P.
Lenihan, Colin R.
et al.
Permanent link: http://hdl.handle.net/10197/5584
Date: Dec-2010
Abstract: Background & Aims: Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved. Methods: The effect of genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes on the development of dextran sulphate sodium (DSS)–induced colitis was examined in mice. Results: PHD1−/−, but not PHD2+/− or PHD3−/−, mice were less susceptible to the development of colitis than wild-type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of PHD1−/− mice to colitis was associated with increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Furthermore, with the use of cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apo tosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from patients with IBD and in colonic tissues from DSS-treated mice. Conclusions: These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD.
Type of material: Journal Article
Publisher: Elsevier - WB Saunders
Copyright (published version): 2010 Elsevier - WB Saunders
Keywords: ColitisHydroxylaseApoptosisHypoxia
DOI: 10.1053/j.gastro.2010.06.068
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection

Show full item record

SCOPUSTM   
Citations 5

97
Last Week
0
Last month
checked on Sep 17, 2018

Google ScholarTM

Check

Altmetric


This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. For other possible restrictions on use please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.