The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis
The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis
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DOI：
10.1053/j.gastro.2007.10.012
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发表时间：
2008-01-01
期刊：
影响因子：
29.4
通讯作者：
Taylor, Cormac T.
中科院分区：
文献类型：
--
作者：
Cummins, Eoin P.;Seeballuck, Fergal;Taylor, Cormac T.
背景和目的：脯氨酰和天冬酰胺酰羟化酶是关键的氧敏感酶，赋予转录调控途径缺氧敏感性，包括缺氧诱导因子 1 (HIF-1) 和核因子 kappa B (NF-kappa B)。敲除肠上皮细胞中的 HIF-1 或（IKK β 依赖性）NF-κ B 通路会促进小鼠结肠炎模型中的炎症性疾病。 HIF-1 和 NF-kappa B 通路均通过关键调节分子的羟基化而受到羟化酶作用的抑制。方法：在本研究中，我们在体外和葡聚糖硫酸钠诱导的小鼠结肠炎模型中研究了羟化酶抑制剂二甲基乙二酰甘氨酸 (DMOG) 对 Caco-2 肠上皮细胞的影响。结果：DMOG 在培养的肠上皮细胞中诱导 HIF-1 和 NF-κ B 活性，并且对葡聚糖硫酸钠结肠炎具有深刻的保护作用，其方式至少部分反映在肠上皮细胞中抗凋亡表型的发展上，我们认为这可以减少上皮屏障功能障碍。结论：这些数据表明羟化酶抑制剂如 DMOG 代表了治疗炎症性肠病的新策略。
Background & Aims: Prolyl and asparaginyl hydroxylases are key oxygen-sensing enzymes that confer hypoxic sensitivity to transcriptional regulatory pathways including the hypoxia inducibl e factor 1 (HIF-1) and nuclear factor-kappa B (NF-kappa B). Knockout of either HIF-1 or (IKK beta-dependent) NF-kappa B pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappa B pathways are repressed by the action of hydroxylases through the hydroxylation of key regulatory molecules. Methods: In this study we have investigated the effects of the hydroxylase inhibitor dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial cells in vitro and in a dextran sodium sulfate-induced model of murine colitis. Results: DMOG induces both HIF-1 and NF-kappa B activity in cultured intestinal epithelial cells, and is profoundly protective in dextran-sodium sulfate colitis in a manner that is at least in part reflected by the development of an anti-apoptotic phenotype in intestinal epithelial cells, which we propose reduces epithelial barrier dysfunction. Conclusions: These data show that hydroxylase inhibitors such as DMOG represent a new strategy for the treatment of inflammatory bowel disease.