Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function

Tambuwala, Murtaza, Cummins, E.P., Lenihan, C.R. , Kiss, J., Stauch, M., Scholz, C.C., Fraisl, P., Lasitschka, F., Mollenhauer, M., Saunders, S.P., Maxwell, P.H., Carmeliet, P., Fallon, P.G., Schneider, M. and Taylor, C.T. (2010) Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology, 139 (6). pp. 2093-2101. ISSN 0016-5085

Full content URL: https://doi.org/10.1053/j.gastro.2010.06.068

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Item Type:Article
Item Status:Live Archive


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 apoptosis 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. © 2010 AGA Institute.

Additional Information:cited By 145
Keywords:dextran sulfate, dimethyloxalylglycine, interleukin 1beta, interleukin 6, myeloperoxidase, oxygenase inhibitor, procollagen proline 2 oxoglutarate 4 dioxygenase, prolyl hydroxylase 1, small interfering RNA, tumor necrosis factor alpha, unclassified drug, animal cell, animal experiment, animal model, animal tissue, apoptosis, article, cell culture, cell density, colitis, colon, controlled study, disease activity, disease predisposition, disease severity, enteritis, enzyme inhibition, epithelium cell, gene deletion, gene loss, histology, human, human tissue, intestine, mouse, neutrophil chemotaxis, nonhuman, priority journal, protein expression, weight reduction
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
Divisions:College of Science > Lincoln Medical School
ID Code:51669
Deposited On:14 Sep 2022 15:42

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