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dc.contributor.authorFALLON, PADRAICen
dc.contributor.authorSAUNDERS, SEANen
dc.date.accessioned2010-12-09T17:30:48Z
dc.date.available2010-12-09T17:30:48Z
dc.date.issued2010en
dc.date.submitted2010en
dc.identifier.citationMurtaza M. Tambuwala, Eoin P. Cummins, Colin R. Lenihan, Judith Kiss, Markus Stauch, Carsten C. Scholz, Peter Fraisl, Felix Lasitschka, Martin Mollenhauer, Sean P. Saunders, Patrick H. Maxwell, Peter Carmeliet, Padraic G. Fallon, Martin Schneider, Cormac T. Taylor, Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function, Gastroenterology, 139, 6, 2010, 2093-2101en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/41265
dc.descriptionPUBLISHEDen
dc.description.abstractBackground and Aims: 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 enzymes (PHD) 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 due to decreased levels of apoptosis resulting in enhanced epithelial barrier function. Furthermore, using cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apoptosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from IBD patients 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.en
dc.format.extent2093-2101en
dc.language.isoenen
dc.relation.ispartofseriesGastroenterologyen
dc.relation.ispartofseries139en
dc.relation.ispartofseries6en
dc.rightsYen
dc.subjectGastroenterologyen
dc.subjectcolitisen
dc.titleLoss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier functionen
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/pfallonen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/saundesen
dc.identifier.rssinternalid67381en
dc.subject.TCDThemeImmunology, Inflammation & Infectionen
dc.identifier.rssurihttp://dx.doi.org/10.1053/j.gastro.2010.06.068en
dc.contributor.sponsorScience Foundation Ireland (SFI)en


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