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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在人中性粒细胞和巨噬细胞中从 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是保护性的，但不受限制的中性粒细胞聚集会导致附带的组织损伤和炎症。分解素由 omega-3 必需多不饱和脂肪酸生物合成，是免疫细胞在分解阶段产生的信号分子家族，旨在协调恢复稳态。了解控制这些强效分子生物合成的机制可以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，我们利用全合成制备的材料以及基于液相色谱和串联质谱的匹配研究，确定了7,8(S,S)-环氧四烯中间体在resolvin D1、resolvin D2和resolvin D2生物合成中的作用。 resolvin 缀合物在人类吞噬细胞组织再生 (RCTR1) 中的作用。我们证明，这种含 7,8(S,S)-环氧基的中间体可被人 M2 样巨噬细胞直接转化为 resolvin D2，并可被人巨噬细胞、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) 均分别催化该环氧化物转化为 resolvin D1 和 RCTR1。 MS 3 离子阱扫描以及使用 sEH 将 H 218 O 中的 18 O 掺入同位素表明 Resolvin D1 中 C-8 处的氧原子源自水。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 resolvin D1 的 5-脂氧合酶产生一致。 总之，这些结果直接证明了 resolvin 7,8(S,S)-环氧四烯中间体在人类吞噬细胞内源性形成溶解相介质 resolvin D1、resolvin D2 和 RCTR1 中的作用。