Status: Funded - Closed
Statin inhibition of microparticle-mediated inflammation and endothelial dysfunction in sickle cell disease
Christopher McKinney, M.D.
BACKGROUND: Sickle cell disease affects 1 in 400 African American children causing recurrent painful crises and limits lifespan. There have been few advances in the treatment or prevention of these crises since the advent of hydroxyurea. Microparticles have recently been implicated in the inflammatory pathophysiology of sickle cell disease and are potentially targetable by statin therapy.
GAP: Circulating microparticles increase in patients with sickle cell disease during painful vaso-occlusive crises. Statins have been shown to inhibit microparticle formation in a variety of other diseases. Little is known, however, about the effect or mechanism of simvastatin on the inflammatory pathophysiology of sickle cell disease.
HYPOTHESIS: We hypothesize that statins inhibits inflammatory microparticle-mediated neutrophil priming and endothelial cell activation in patients with sickle cell disease.
METHODS: Using plasma obtained from patients with sickle cell disease during steady state and painful crisis, we isolate microparticles through differential centrifugation. We then study the effect of these microparticles on neutrophil priming and endothelial cell activation in the presence of varying concentrations of simvastatin.
RESULTS: We have demonstrated increased microparticle formation in sickle cell patients during acute vaso-occlusive crises and episodes of the acute chest syndrome. PMN priming by MPs is increased during VOC. Preliminary data suggest that simvastatin has mild inhibitory effect on neutrophil priming and endothelial cell activation.
IMPACT: This pre-clinical data shows a mild inhibitory effect of simvastatin on neutrophil priming and endothelial cell activation involved in systemic inflammation. This provides some support for future clinical trials looking at chronic simvastatin therapy on rate and duration of vaso-occlusive crises.
University of Colorado Denver