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Resolvin D4 attenuates the severity of pathological thrombosis in mice

Deya Cherpokova, Charlotte Camille Jouvene, Stephania Libreros, Elise DeRoo, Long Chu, Xavier de la Rosa, Paul Norris, Denisa D Wagner and Charles N. Serhan

Key Points

  • Specialized pro-resolving mediators are temporally biosynthesized during venous thrombosis progression.

  • Resolvin D4 reduces existent venous thrombosis burden in mice.

Abstract

Deep vein thrombosis (DVT) is a common cardiovascular disease with a major impact 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 (LC-MS/MS)‑based metabololipidomics approach, we established temporal clusters of endogenously biosynthesized specialized pro-resolving 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 pro-resolving 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.

  • Submitted November 15, 2018.
  • Revision received July 11, 2019.
  • Accepted July 3, 2019.