title: Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-β1 signaling. [corrected].
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.
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.|School of Medicine and Medical Science, Charles Institute of Dermatology, University College Dublin, Dublin, Ireland.
authors: Mario C
authors: MC
authors: Manresa
authors: School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, Northerm Ireland.
authors: Murtaza M
authors: MM
authors: Tambuwala
authors: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Praveen
authors: P
authors: Radhakrishnan
authors: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Jonathan M
authors: JM
authors: Harnoss
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors: Eric
authors: E
authors: Brown
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.|Systems Biology Ireland, University College Dublin, Dublin, Ireland; and.
authors: Miguel A
authors: MA
authors: Cavadas
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors: Ciara E
authors: CE
authors: Keogh
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.|Systems Biology Ireland, University College Dublin, Dublin, Ireland; and.
authors: Alex
authors: A
authors: Cheong
authors: Department of Medicine and Biomedical Sciences Ph.D. Program, University of California, San Diego, School of Medicine, La Jolla, California.
authors: Kim E
authors: KE
authors: Barrett
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors: Eoin P
authors: EP
authors: Cummins
authors: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Martin
authors: M
authors: Schneider
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland; Cormac.Taylor@UCD.ie.|Systems Biology Ireland, University College Dublin, Dublin, Ireland; and.
authors: Cormac T
authors: CT
authors: Taylor
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; D003094:Collagen; D006899:Mixed Function Oxygenases; D048049:Extracellular Signal-Regulated MAP Kinases; C040947:oxalylglycine
keywords: hydroxylase inhibition; hypoxia; inflammatory bowel disease; intestinal fibrosis; transforming growth factor-β1 (TGF-β1) signaling