期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 311, 期 6, 页码 G1076-G1090出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00229.2016
关键词
hypoxia; inflammatory bowel disease; intestinal fibrosis; hydroxylase inhibition; transforming growth factor-beta 1 (TGF-beta 1) signaling
资金
- Science Foundation Ireland [SFI: 11/PI/1005]
- Deutsche Forschungsgemeinschaft
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-beta 1 is a key regulator of fibrosis that acts through the activation of fibroblasts. Hydroxylase inhibition reduced TGF-beta 1-induced expression of fibrotic markers in cultured fibroblasts, suggesting a direct role for hydroxylases in TGF-beta 1 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-beta 1-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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