Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-β1 signaling
Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease, a condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition of oxygen-sensing prolyl hydroxylases, which confer oxygen sensitivity upon the hypoxi...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
October 27, 2016
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| In: |
American journal of physiology. Gastrointestinal and liver physiology
Year: 2016, Volume: 311, Issue: 6, Pages: G1076-G1090 |
| ISSN: | 1522-1547 |
| DOI: | 10.1152/ajpgi.00229.2016 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1152/ajpgi.00229.2016 Verlag, lizenzpflichtig, Volltext: https://journals.physiology.org/doi/full/10.1152/ajpgi.00229.2016 
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| Author Notes: | Mario C. Manresa, Murtaza M. Tambuwala, Praveen Radhakrishnan, Jonathan M. Harnoss, Eric Brown, Miguel A. Cavadas, Ciara E. Keogh, Alex Cheong, Kim E. Barrett, Eoin P. Cummins, Martin Schneider, and Cormac T. Taylor |
| Summary: | Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease, a condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition of oxygen-sensing prolyl hydroxylases, which confer oxygen sensitivity upon the hypoxia-inducible factor 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 a 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 ameliorated fibrosis. TGF-β1 is a key regulator of fibrosis that 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 signaling. This was at least in part due to inhibition of noncanonical activation of extracellular signal-regulated kinase (ERK) signaling. 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 profibrotic pathways. |
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| Item Description: | Gesehen am 07.05.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1522-1547 |
| DOI: | 10.1152/ajpgi.00229.2016 |