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

Abstract

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<i>R</i>-resolvin D1 (17<i>R-</i>RvD1; 7<i>S</i>, 8<i>R</i>, 17<i>R</i>-trihydroxy-4<i>Z</i>, 9<i>E</i>, 11<i>E</i>, 13<i>Z</i>, 15<i>E</i>, 19<i>Z</i>-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<i>R</i> <i>-</i>RvD1 reduces systemic/local inflammation and vascular dysfunction in lung and kidney. The mechanism of action of 17<i>R</i>-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<i>R</i>-RvD1 might represent a new therapeutic strategy for the inflammatory vasculopathy of SCD.