Impact of Hydroxylase inhibitors on fibrosis associated with IBD

Mario Cabrero Manresa, Murtaza Tambuwala, Miguel Cavadas, Eoin Cummins, Alex Cheong, Cormac Taylor

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Fibrosis is a major complication of inflammatory bowel disease (IBD) which cannot be adequately addressed with pharmacologic therapy. In IBD the treatment of fibrosis usually requires surgical resection of colonic segments and is responsible for 75% of surgical interventions in Crohn’s disease (CD). Pharmacological inhibition of hydroxylases ameliorates inflammation in multiple models of IBD. We hypothesized that hydroxylase inhibition may also impact fibrosis in IBD. To test this, the effect of the hydroxylase inhibitor DMOG was tested using an in vivo model of IBD. Mice given 2.5% dextran sodium sulphate (DSS) in drinking water for 5 days and allowed natural recovery for 14 days, developed inflammation and fibrosis, as shown by higher inflammation score, higher submucosal collagen-I deposition and increased fibroblast infiltration through the colonic mucosa. Mice treated with intra peritoneal DMOG, exhibited less inflammation and lower collagen accumulation, as well as reduced fibroblast infiltration. To test whether this antifibrotic action was secondary to the anti-inflammatory effect or due to a direct anti fibrotic action, an in vitro model was used. Fibroblasts were treated with TGF-β1, the key mediator of healing and fibrosis. DMOG was given to the cells prior to TGF-β1, and α-smooth muscle actin (α-SMA) and collagen-I were analyzed as key fibrosis markers. Both markers were reduced by hydroxylase inhibitors in the presence of TGF-β1, suggesting a direct antifibrotic action in fibroblasts. Furthermore, this effect was related to a reduced expression of Smad-3 in human colonic fibroblast, a central effector of the TGF-β pathway. In conclusion, hydroxylase inhibition reduces fibrosis in vitro and in vivo affecting, at least in part, the TGF-β pathway. That could be a starting point to search for therapies that can ameliorate fibrosis in this and other diseases.
Original languageEnglish
Title of host publicationUnknown Host Publication
PublisherFederation of American Societies for Experimental Biology
PagesLB789-LB789
Number of pages1
Volume28
Publication statusPublished - 1 Apr 2014
EventHypoxia -
Duration: 1 Apr 2014 → …

Conference

ConferenceHypoxia
Period1/04/14 → …

Keywords

  • Inflammatory bowel disease
  • hydroxylases
  • fibrosis

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