While the acute inflammatory response to harmful stimuli is protective, unrestrained neutrophil swarming drives collateral tissue damage and inflammation. Biosynthesized from omega-3 essential polyunsaturated fatty acids, resolvins are a family of signaling molecules produced by immune cells within the resolution phase to orchestrate return to homeostasis. Understanding the mechanisms that govern biosynthesis of these potent molecules gives insight into stimulating endogenous resolution and offers fresh opportunities for preventing and treating excessive inflammation. In this report, using materials prepared by total synthesis and liquid chromatography and tandem mass spectrometry-based matching studies, we established the role of 7,8(S,S)-epoxytetraene intermediate in the biosynthesis of resolvin D1, resolvin D2, and the resolvin conjugate in tissue regeneration (RCTR1) by human phagocytes. We demonstrated that this 7,8(S,S)-epoxy-containing intermediate is directly converted to resolvin D2 by human M2-like macrophages and to resolvin D1 and RCTR1 by human macrophages, neutrophils, and peripheral blood mononuclear cells. In addition, both human recombinant soluble epoxide hydrolase (sEH) and the glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) each catalyze conversion of this epoxide to resolvin D1 and RCTR1, respectively. MS 3 ion-trap scans and isotope incorporation of 18 O from H 2 18 O with sEH indicated that the oxygen atom at C-8 in resolvin D1 is derived from water. Results from molecular docking simulations with biosynthetic precursor 17S-hydroperoxy-4,7,10,13,19- cis -15- trans -docosahexaenoic acid and the epoxy intermediate were consistent with 5-lipoxygenase production of resolvin D1. Together, these results give direct evidence for the role of resolvin 7,8(S,S)-epoxytetraene intermediate in the endogenous formation of resolution-phase mediators resolvin D1, resolvin D2, and RCTR1 by human phagocytes.

中文翻译：

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从人中性粒细胞和巨噬细胞中 7,8（S，S）-环氧四烯生物合成 resolvin D1、resolvin D2 和 RCTR1


虽然对有害刺激的急性炎症反应具有保护性，但不受约束的中性粒细胞蜂群会驱动侧支组织损伤和炎症。消退素由 omega-3 必需多不饱和脂肪酸生物合成，是免疫细胞在消退阶段产生的一个信号分子家族，用于协调恢复体内平衡。了解控制这些有效分子生物合成的机制有助于深入了解刺激内源性消退，并为预防和治疗过度炎症提供新的机会。在本报告中，使用通过全合成和液相色谱以及基于串联质谱的匹配研究制备的材料，我们确定了 7,8（S，S）-环氧四烯中间体在人吞噬细胞组织再生 （RCTR1） 中 resolvin D1、resolvin D2 和 resolvin 偶联物的生物合成中的作用。我们证明，这种含 7,8（S，S） 环氧树脂的中间体被人 M2 样巨噬细胞直接转化为 resolvin D2，被人巨噬细胞、中性粒细胞和外周血单核细胞直接转化为 resolvin D1 和 RCTR1。此外，人重组可溶性环氧化物水解酶 （sEH） 和谷胱甘肽 S-转移酶白三烯 C 4 合酶 （LTC 4 S） 分别催化这种环氧化物转化为消解蛋白 D1 和 RCTR1。MS 3 离子阱扫描和来自 H 218 O 的 18 O 与 sEH 的同位素掺入表明，解析素 D1 中 C-8 位点的氧原子来自水。与生物合成前体 17S-氢过氧-4,7,10,13,19-顺式-15-反式-二十二碳六烯酸和环氧中间体的分子对接模拟结果与解决素 D1 的 5-脂氧合酶产生一致。 总之，这些结果为解析蛋白 7,8（S，S）-环氧四烯中间体在人吞噬细胞解析蛋白 D1、解析蛋白 D2 和 RCTR1 的内源性形成中的作用提供了直接证据。