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Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-β1 signaling. [corrected].

Author information

Affiliations

  • 1. School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
      Authors
    • Manresa MC 1
    • Brown E 1
    • Cavadas MA 1
    • Keogh CE 1
    • Cheong A 1
    • Cummins EP 1
    (6 authors)
  • 2. School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, Northerm Ireland.
      Authors
    • Tambuwala MM 2
    (1 author)
  • 3. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
      Authors
    • Radhakrishnan P 3
    • Harnoss JM 3
    • Schneider M 3
    (3 authors)
  • 4. Department of Medicine and Biomedical Sciences Ph.D. Program, University of California, San Diego, School of Medicine, La Jolla, California.
      Authors
    • Barrett KE 4
    (1 author)
  • 5. School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland;
      Authors
    • Taylor CT 5
    (1 author)

ORCIDs linked to this article

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American Journal of physiology. Gastrointestinal and Liver Physiology, 27 Oct 2016, 311(6):G1076-G1090
https://doi.org/10.1152/ajpgi.00229.2016 PMID: 27789456 

This article has been corrected. See Am J Physiol Gastrointest Liver Physiol. 2017 Apr 1;312(4):G405.

Abstract 

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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Read article at publisher's site: https://doi.org/10.1152/ajpgi.00229.2016

Read article for free, from open access legal sources, via Unpaywall: https://www.physiology.org/doi/pdf/10.1152/ajpgi.00229.2016Unpaywall

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Deutsche Forschungsgemeinschaft (DFG)

    Science Foundation Ireland (SFI) (1)