Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease (IBD). Fibrosis is responsible for 75% of surgical interventions in IBD. Pharmacological inhibition of O2 sensing hydroxylases ameliorates inflammation in 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 investigated. Mice exposed to 2.5% dextran sodium sulphate in drinking water for 5 days and allowed to recover for 14 days, developed colon fibrosis reflected by an altered pattern of submucosal collagen deposition, increased fibroblast infiltration and higher expression of Smad3. Mice treated with DMOG exhibited lower submucosal collagen accumulation, reduced fibroblast infiltration and less Smad3 positive staining. An in vitro model was then used to investigate the mechanism of the anti-fibrotic action of DMOG. Fibroblasts were treated with TGF-β1, key mediator of fibrosis. DMOG was given to the cells prior to TGF-β1, and α-smooth muscle actin (α-SMA) and collagen-I were analyzed as markers of fibrosis. TGF-β1 induced phenotypic changes associated to higher expression of collagen-I and α-SMA. Both markers were reduced in DMOG treated cells, suggesting an inhibition of TGF-β1 mediated fibroblast activation. We further investigated the impact of DMOG upon TGF-β1 signalling. DMOG did not affect Smad2/3 (canonical) TGF dependent phosphorylation. In contrast, it reduced TGF-β1 dependent ERK (non canonical) phosphorylation. In conclusion, hydroxylase inhibition reduces fibrosis in vitro and in vivo, at least in part, through the inhibition of non canonical TGF-β signalling.
|Number of pages||1|
|Publication status||Published - 1 Apr 2015|
Manresa, M. C., Tambuwala, M. M., Cavadas, M. S., Cummins, E. P., Cheong, A., & Taylor, C. T. (2015). The impact of hydroxylase inhibition on TGF-beta 1 induced fibrosis associated with inflammatory bowel disease. Experimental Dermatology, 24(12), 984-984. https://www.fasebj.org/doi/abs/10.1096/fasebj.29.1_supplement.lb689