Resolution of sickle cell disease-associated inflammation and tissue damage with 17R-resolvin D1.
Alessandro MatteAntonio RecchiutiEnrica FedertiBérengère KoehlThomas MintzWassim El NemerPierre-Louis TharauxValentine BrousseImmacolata AndolfoAlessia LamolinaraOlga WeinbergAngela SicilianoPaul C NorrisIan R RileyAchille IolasconCharles Nicholas SerhanCarlo BrugnaraLucia De FranceschiPublished in: Blood (2018)
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 17R-resolvin D1 (17R-RvD1; 7S, 8R, 17R-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-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 17R -RvD1 reduces systemic/local inflammation and vascular dysfunction in lung and kidney. The mechanism of action of 17R-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, 17R-RvD1 might represent a new therapeutic strategy for the inflammatory vasculopathy of SCD.
Keyphrases
- sickle cell disease
- oxidative stress
- endothelial cells
- induced apoptosis
- poor prognosis
- high fat diet induced
- signaling pathway
- acute myocardial infarction
- type diabetes
- vascular endothelial growth factor
- gene expression
- coronary artery disease
- dna methylation
- adipose tissue
- immune response
- escherichia coli
- long non coding rna
- inflammatory response
- subarachnoid hemorrhage
- monoclonal antibody
- toll like receptor