SELSEHCC

Vascular pathology in sickle cell disease – SCiF 2013

Paul S. Frenette: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research of Albert Einstein College of Medicine, USA

Sickle cell disease (SCD) is a proinflammatory disease triggered by alterations of the red blood cell (RBC) membrane due to repetitive cycles of hemoglobin S polymerization. Our intravital microscopy studies in humanized models of SCD have revealed that vaso-occlusion (VOC) is induced by adherent leukocytes in venules of the microcirculation. Inhibition of endothelial selectins, adhesion molecules critical for the recruitment of leukocytes, prevented VOC and improved the survival of SCD mice subjected to lethal VOC. Further studies using multichannel fluorescence analyses to dissect these dynamic interactions have revealed that neutrophils underwent a second wave of activation signals mediated by E-selectin binding and Src activation, and leading to the activation of the integrin Mac1 at the leading edge of crawling neutrophils, allowing the capture of circulating RBCs which then produces blockage of flow. Inhibition of E-selectin or Mac1 significantly prevented VOC, suggesting that they represent potential therapeutic targets.  Indeed, we have found that a pan-selectin antagonist, GMI-1070, which largely blocks E-selectin function, prevented VOC by inhibiting neutrophil activation and Mac1-mediated RBC capture.  GMI-1070 is currently undergoing clinical evaluation in a multicenter trial. On the other hand, the ligation of Fc receptors (FcRIII) expressed on neutrophils, following the administration of intravenous immunoglobulins (IVIG), sends inhibitory signals via the recruitment of the phosphatase SHP-1 that can reverse E-selectin-mediated activation of Mac-1 and VOC.  IVIG is also evaluated in clinical trials. Recent results suggest that this activating pathway can also be altered by phosphodiesterase 9 (PDE9) inhibition which prevent cyclic guanosine monophosphate (cGMP) degradation and lead to reduced leukocyte activation and improved blood flow in the VOC model.  Interestingly, hydroxyurea, a nitic oxide donor activating cGMP signaling had similar inhibitory effects on leukocyte activation, suggesting that its acute administration in the setting of VOC may have beneficial effects.  These data support the notion that modulation of leukocyte activation may improve VOC.

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