Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, BTM 3016, Boston, MA, 02115, USA.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, BTM 3016, Boston, MA, 02115, USA.
Biochem Biophys Res Commun. 2018 Oct 7;504(3):553-561. doi: 10.1016/j.bbrc.2018.03.037. Epub 2018 Mar 15.
Metabolomics enables a systems approach to interrogate the bioactive mediators, their pathways and further metabolites involved in the physiology and pathophysiology of human and animal tissues. New metabololipidomic approaches with mass spectrometry presented in this brief review can now be utilized for the identification and profiling of lipid mediator networks that control inflammation-resolution in human blood and healthy and diseased solid tissues. Coagulation of blood is a protective response that prevents excessive bleeding on injury of blood vessels. Here, we review novel approaches to understand the relationship(s) between coagulation and resolution of inflammation and infection. To determine whether coagulation is involved in host-protective actions by lipid mediators, we used a metabololipidomic-based profiling approach with human whole blood (WB) during coagulation. We identified recently temporal clusters of endogenously produced pro-thrombotic and proinflammatory lipid mediators (eicosanoids), as well as specialized proresolving mediators (SPMs) in this vital process. In addition to the classic eicosanoids (prostaglandins, thromboxanes and leukotrienes), a specific SPM cluster was identified that consists of resolvin E1 (RvE1), RvD1, RvD5, lipoxin B, and maresin 1, each of which present at bioactive concentrations (0.1-1 nM). The removal of adenosine from coagulating blood samples significantly enhances SPM amounts and unleashes the biosynthesis of RvD3, RvD4, and RvD6 evident following rapid snap freezing with centrifugation before extraction and LC-MS-MS. The classic cyclooxygenase inhibitors, celecoxib and indomethacin, that block thromboxanes and prostanoids do not block production of the clot-driven SPM cluster. Unbiased mass cytometry analysis demonstrated that the SPM cluster produced in human blood targets leukocytes at the single-cell level, directly activating extracellular signaling in human neutrophils and monocytes. Human whole blood treated with the components of this SPM cluster enhanced both phagocytosis and killing of Escherichia coli by leukocytes. Thus, we identified a pro-resolving lipid mediator circuit and specific SPM cluster that promotes host defense. This new lipid mediator (LM)-SPM metabololipidomic approach now provides accessible metabolomic profiles in healthy and diseased human tissues, including cancer, for precision and personalized medicine.
代谢组学能够系统地研究生物活性介质及其途径，以及参与人和动物组织生理和病理生理学的进一步代谢物。本综述介绍了采用质谱的新型代谢脂质组学方法，现在可用于鉴定和分析控制人血液和健康及患病实体组织中炎症消退的脂质介质网络。血液凝结是一种保护反应，可防止血管损伤后过度出血。在这里，我们综述了理解凝血与炎症和感染消退之间关系的新方法。为了确定脂质介质的凝血是否参与宿主的保护作用，我们在凝血过程中使用基于代谢脂质组学的人全血（WB）分析方法。我们鉴定了内源性产生的促血栓形成和促炎脂质介质（类二十烷酸）以及特定的促解决介质（SPM）的新的时间聚类。除了经典的类二十烷酸（前列腺素、血栓烷和白三烯）外，还鉴定了一个特定的 SPM 聚类，该聚类由 17-去氢前列腺素 E1（RvE1）、RvD1、RvD5、脂氧素 B 和maresin 1 组成，每种物质均以生物活性浓度（0.1-1 nM）存在。从凝结的血液样本中去除腺苷可显著增加 SPM 含量，并释放出 RvD3、RvD4 和 RvD6 的生物合成，这在快速冷冻后通过离心进行提取和 LC-MS-MS 前立即显现出来。经典的环氧化酶抑制剂塞来昔布和吲哚美辛可阻断血栓烷和前列腺素的生成，但不能阻断凝血驱动的 SPM 聚类的产生。无偏质谱分析表明，在人类血液中产生的 SPM 聚类可在单细胞水平上靶向白细胞，直接激活人中性粒细胞和单核细胞的细胞外信号。用 SPM 聚类的成分处理的人类全血增强了白细胞对大肠杆菌的吞噬和杀伤作用。因此，我们鉴定了一个促解决的脂质介质回路和特定的 SPM 聚类，该聚类可促进宿主防御。这种新的脂质介质（LM）-SPM 代谢脂质组学方法现在为健康和患病的人体组织（包括癌症）提供了可及的代谢组学图谱，为精准医学和个性化医疗提供了支持。
