Resolution of sickle cell disease-associated inflammation and tissue damage with 17-resolvin D1.

Resolvins (Rvs), endogenous lipid mediators, play a key role in the resolution of inflammation. Sickle cell disease (SCD), a genetic disorder of hemoglobin, is characterized by inflammatory and vaso-occlusive pathologies. We document altered proresolving events following hypoxia/reperfusion in humanized SCD mice. We demonstrate novel protective actions of 17-resolvin D1 (17RvD1; 7, 8, 17-trihydroxy-4, 9, 11, 13, 15, 19-docosahexaenoic acid) in reducing ex vivo human SCD blood leukocyte recruitment by microvascular endothelial cells and in vivo neutrophil adhesion and transmigration. In SCD mice exposed to hypoxia/reoxygenation, oral administration of 17 RvD1 reduces systemic/local inflammation and vascular dysfunction in lung and kidney. The mechanism of action of 17-RvD1 involves (1) enhancement of SCD erythrocytes and polymorphonuclear leukocyte efferocytosis, (2) blunting of NF-κB activation, and (3) a reduction in inflammatory cytokines, vascular activation markers, and E-selectin expression. Thus, 17-RvD1 might represent a new therapeutic strategy for the inflammatory vasculopathy of SCD.