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


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

Publication DOI: https://doi.org/10.1152/ajpgi.00229.2016
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences
Additional Information: © APS
Uncontrolled Keywords: hypoxia,inflammatory bowel disease,intestinal fibrosis,hydroxylase inhibition,transforming growth factor-b1 signaling
Publication ISSN: 1522-1547
Last Modified: 17 Jun 2024 07:22
Date Deposited: 27 Oct 2016 12:30
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Related URLs: http://ajpgi.ph ... jpgi.00229.2016 (Publisher URL)
PURE Output Type: Article
Published Date: 2016-12-01
Published Online Date: 2016-10-27
Accepted Date: 2016-10-09
Submitted Date: 2016-06-21
Authors: Manresa, Mario Cabrero
Tambuwala, Murtaza M.
Rhadakrishnan, Praveen
Harnoss, Jonathan M.
Brown, Eric
Cavadas, Miguel A.
Keogh, Ciara E.
Cheong, Alex (ORCID Profile 0000-0003-2482-9078)
Barrett, Kim E.
Cummins, Eoin P.
Schneider, Martin
Taylor, Cormac T.



Version: Accepted Version

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