Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.
Department of Pediatrics, Harvard Medical School, Boston, MA.
Blood. 2019 Oct 24;134(17):1458-1468. doi: 10.1182/blood.2018886317.
Deep vein thrombosis (DVT) is a common cardiovascular disease with a major effect on quality of life, and safe and effective therapeutic measures to efficiently reduce existent thrombus burden are scarce. Using a comprehensive targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics approach, we established temporal clusters of endogenously biosynthesized specialized proresolving mediators (SPMs) and proinflammatory and prothrombotic lipid mediators during DVT progression in mice. Administration of resolvin D4 (RvD4), an SPM that was enriched at the natural onset of thrombus resolution, significantly reduced thrombus burden, with significantly less neutrophil infiltration and more proresolving monocytes in the thrombus, as well as an increased number of cells in an early apoptosis state. Moreover, RvD4 promoted the biosynthesis of other D-series resolvins involved in facilitating resolution of inflammation. Neutrophils from RvD4-treated mice were less susceptible to an ionomycin-induced release of neutrophil extracellular traps (NETs), a meshwork of decondensed chromatin lined with histones and neutrophil proteins critical for DVT development. These results suggest that delivery of SPMs, specifically RvD4, modulates the severity of thrombo-inflammatory disease in vivo and improves thrombus resolution.
深静脉血栓形成（DVT）是一种常见的心血管疾病，对生活质量有重大影响，目前缺乏安全有效的治疗措施来有效减少现有的血栓负担。本研究采用全面的靶向液相色谱-串联质谱代谢脂质组学方法，在小鼠 DVT 进展过程中建立了内源性生物合成的特异性促解决介质（SPM）以及促炎和促血栓脂质介质的时间聚类。在血栓自然消退的起始时富集的 SPM 之一，即 resolvin D4（RvD4）的给药可显著降低血栓负担，血栓中中性粒细胞浸润减少，促解决单核细胞增多，以及处于早期凋亡状态的细胞数量增加。此外，RvD4 促进了参与炎症消退的其他 D 系列 resolvin 的生物合成。与未用 RvD4 处理的小鼠的中性粒细胞相比，用 RvD4 处理的小鼠的中性粒细胞不易发生离子霉素诱导的中性粒细胞胞外陷阱（NETs）释放，NETs 是一种由去凝聚的染色质与组蛋白以及对 DVT 发展至关重要的中性粒细胞蛋白组成的网格。这些结果表明，SPM 的给药，特别是 RvD4，可调节体内血栓炎症性疾病的严重程度并改善血栓溶解。
