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1.
Blood ; 133(3): 252-265, 2019 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-30404812

RESUMEN

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.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Antiinflamatorios no Esteroideos/administración & dosificación , Ácidos Docosahexaenoicos/administración & dosificación , Enfermedades Renales/prevención & control , Neumonía/prevención & control , Animales , Citocinas/metabolismo , Humanos , Enfermedades Renales/etiología , Enfermedades Renales/patología , Ratones , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Neumonía/etiología , Neumonía/patología
2.
Cells ; 9(6)2020 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-32466566

RESUMEN

Few data-driven metabolomic approaches have been reported in sickle cell disease (SCD) to date. We performed a metabo-lipidomic study on the plasma and red blood cells of a steady-state mouse model carrying the homozygous human hemoglobin SS, compared with AS and AA genotypes. Among the 188 metabolites analyzed by a targeted quantitative metabolomic approach, 153 and 129 metabolites were accurately measured in the plasma and red blood cells, respectively. Unsupervised PCAs (principal component analyses) gave good spontaneous discrimination between HbSS and controls, and supervised OPLS-DAs (orthogonal partial least squares-discriminant analyses) provided highly discriminant models. These models confirmed the well-known deregulation of nitric oxide synthesis in the HbSS genotype, involving arginine deficiency and increased levels of dimethylarginines, ornithine, and polyamines. Other discriminant metabolites were newly evidenced, such as hexoses, alpha-aminoadipate, serotonin, kynurenine, and amino acids, pointing to a glycolytic shift and to the alteration of metabolites known to be involved in nociceptive pathways. Sharp remodeling of lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins was evidenced in red blood cells. Our metabolomic study provides an overview of the metabolic remodeling induced by the sickle genotype in the plasma and red blood cells, revealing a biological fingerprint of altered nitric oxide, bioenergetics and nociceptive pathways.


Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/metabolismo , Eritrocitos/metabolismo , Metabolómica , Nocicepción , Animales , Análisis Discriminante , Hemoglobina Falciforme , Heterocigoto , Análisis de los Mínimos Cuadrados , Ratones , Análisis de Componente Principal
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