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Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling

Cabrero Manresa, Mario, Tambuwala, Murtaza M, Radhakrishnan, Praveen, Harnoss, Jonathan M, Brown, Eric, Cavadas, Miguel A, Keogh, Ciara E, Cheong, Alex, Barrett, Kim E., Cummins, Eoin P, Schneider, Martin and Taylor, Cormac T (2016) Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling. American Journal of Physiology - Gastrointestinal and Liver Physiology, 10 . [Journal article]

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URL: http://ajpgi.physiology.org/content/early/2016/10/21/ajpgi.00229.2016

DOI: 10.1152/ajpgi.00229.2016

Abstract

Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease (IBD), a condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition of oxygen-sensing prolyl hydroxylases (PHD), which confer oxygen-sensitivity upon the hypoxia inducible factor (HIF) pathway, has recently been shown to have therapeutic potential in colitis, although the mechanisms involved remain unclear. Here, we investigated the impact of hydroxylase inhibition on inflammation-driven fibrosis in a murine colitis model. Mice exposed to dextran sodium sulfate followed by period of recovery developed intestinal fibrosis characterized by alterations in the pattern of collagen deposition and infiltration of activated fibroblasts. Treatment with the hydroxylase inhibitor dimethyloxalylglycine (DMOG) ameliorated fibrosis. TGF-β1 is a key regulator of fibrosis which acts through the activation of fibroblasts. Hydroxylase inhibition reduced TGF-β1-induced expression of fibrotic markers in cultured fibroblasts suggesting a direct role for hydroxylases in TGF-β1 signalling. This was at least in part due to inhibition of non-canonical activation of extracellular signal-regulated kinase (ERK) signalling. In summary, pharmacologic hydroxylase inhibition ameliorates intestinal fibrosis, through suppression of TGF-β1-dependent ERK activation in fibroblasts. We hypothesize that in addition to previously reported immunosupressive effects, hydroxylase inhibitors independently suppress pro-fibrotic pathways.

Item Type:Journal article
Keywords:hypoxia, inflammatory bowel disease, intestinal fibrosis, Hydroxylase inhibition, Transforming growth factor-b1 signaling
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Pharmacy & Pharmaceutical Sciences
ID Code:36215
Deposited By: Dr Murtaza Tambuwala
Deposited On:07 Nov 2016 11:54
Last Modified:26 Oct 2017 22:23

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