Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2011 Sep 9;286(36):31532-41. doi: 10.1074/jbc.M111.237990. Epub 2011 Jul 12.
Neuroinflammation and traumatic brain injury involve activation of inflammatory cells and production of local pro-inflammatory mediators that can amplify tissue damage. Using LC-UV-MS-MS-based lipidomics in tandem with functional screening at the single-cell level in microfluidic chambers, we identified a series of novel bioactive oxygenated docosahexaenoyl ethanolamide- (DHEA) derived products that regulated leukocyte motility. These included 10,17-dihydroxydocosahexaenoyl ethanolamide (10,17-diHDHEA) and 15-hydroxy-16(17)-epoxy-docosapentaenoyl ethanolamide (15-HEDPEA), each of which was an agonist of recombinant CB2 receptors with EC(50) 3.9 × 10(-10) and 1.0 × 10(-10) M. In human whole blood, 10,17-diHDHEA and 15-HEDPEA at concentrations as low as 10 pM each prevented formation of platelet-leukocyte aggregates involving either platelet-monocyte or platelet-polymorphonuclear leukocyte. In vivo, 15-HEDPEA was organ-protective in mouse reperfusion second organ injury. Together these results indicate that DHEA oxidative metabolism produces potent novel molecules with anti-inflammatory and organ-protective properties.
神经炎症和创伤性脑损伤涉及炎症细胞的激活和局部促炎介质的产生，这些介质可以放大组织损伤。我们使用基于 LC-UV-MS-MS 的脂质组学，并在微流控室中的单细胞水平进行功能筛选，鉴定出一系列新型生物活性氧化二十二碳六烯酰乙醇酰胺（DHEA）衍生产物，这些产物可调节白细胞的迁移。其中包括 10,17-二羟基二十二碳六烯酰乙醇酰胺（10,17-diHDHEA）和 15-羟基-16(17)-环氧二十二碳五烯酰乙醇酰胺（15-HEDPEA），它们均为重组 CB2 受体的激动剂，EC50 分别为 3.9×10(-10) M 和 1.0×10(-10) M。在人全血中，浓度低至 10 pM 的 10,17-diHDHEA 和 15-HEDPEA 可阻止涉及血小板-单核细胞或血小板-多形核白细胞的血小板-白细胞聚集体的形成。在体内，15-HEDPEA 在小鼠再灌注二次器官损伤中具有器官保护作用。这些结果表明，DHEA 氧化代谢产生具有抗炎和器官保护特性的新型有效分子。
