Hydroxylases regulate intestinal fibrosis through the suppression of ERK mediated TGF-β1 signaling.

摘要: Fibrosis is a complication of chronic inflammatory disorders such as bowel disease (IBD), condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition oxygen-sensing prolyl hydroxylases (PHD), confer oxygen-sensitivity upon the hypoxia inducible factor (HIF) pathway, recently been shown to have potential in colitis, although mechanisms involved remain unclear. Here, we investigated impact hydroxylase on inflammation-driven fibrosis murine colitis model. Mice exposed dextran sodium sulfate followed by period recovery developed intestinal characterized alterations pattern collagen deposition infiltration activated fibroblasts. Treatment with inhibitor dimethyloxalylglycine (DMOG) ameliorated fibrosis. TGF-β1 key regulator acts through activation Hydroxylase reduced TGF-β1-induced expression fibrotic markers cultured fibroblasts suggesting direct role for signalling. This was at least part due non-canonical extracellular signal-regulated kinase (ERK) In summary, pharmacologic ameliorates fibrosis, suppression TGF-β1-dependent ERK We hypothesize that addition previously reported immunosupressive effects, inhibitors independently suppress pro-fibrotic pathways