The proposed research will focus on sickle (SS) red cell-endothelial interaction and related vasoocclusion using a combination of perfusion techniques and intravital observations. We will investigate the basis of abnormal red cell interaction with the endothelium in sickle cell disease by emphasizing the potential role of defined hemodynamic, cellular and humoral factors. Experiments are designed to accomplish the following objectives: 1. The role of hemodynamic factors in determining the sites and extent of adhesion with reference to the wall shear rates and microvascular adhesion sites and the effect of adhesion and red cell aggregation on hemodynamic parameters. 2. The role of von Willebrand factor (vWF), other adhesive proteins, and known receptors to these proteins in promotion and inhibition of sickle cell-endothelial interaction. 3. To define the basis for the observed differences in adhesion properties of density-defined classes of sickle cells. To differentiate the role of cellular rigidity (deoxygenation and MCHC) and membrane characteristics in adhesion of density defined SS cell classes. 3. To investigate the role of selected vasoactive stimuli in adhesion. Emphasis will be given to the role of substances which elicit multiple responses in the endothelium (e.g. , histamine, bradykinin, thrombin, etc) and thereby effect the vWF secretion, venular permeability as well as the vascular tone. Also, the effect of known smooth muscle agonists and relaxants will be evaluated. The results of the proposed protocol may provide better understanding of the potential role of adhesion in vasooclusive events in sickle cell disease.
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