Red blood cells (RBCs) play an important role in leukocyte-endothelial (L-E) interactions through the unique suspension theology that they impart to blood. For example, we previously found a 10-fold increase in the number of bound leukocytes when the hematocrit of the cell suspension in a flow chamber was increased from 0 to 30%. This enhancement of cell adhesion in the presence of RBCs was due to physical, rather than biochemical, interactions between the flowing lymphocytes and RBCs. In the first 3 years of this grant, we have shown how mechanical interactions between blood cells contribute to leukocyte rolling and adhesion. We have, for the first time, estimated the hydrodynamic forces exerted in flowing blood that influence cells as they enter postcapillary venules and roll on the endothelium. These studies, performed in relevant geometries, provide a better understanding of the mechanism of leukocyte rolling, and show that vessel geometry and RBC organization play important roles in leukocyte rolling in postcapillary venules. As proposed in the original application, we have demonstrated that there is an optimal configuration of RBCs required to drive the WBC to the wall. In this competing renewal, we extend these studies to investigate the role of blood vessel shape and RBC aggregation in the initiation of leukocyte rolling by examining leukocyte rolling in various tissues in vivo. Mathematical modeling and novel microfabricated networks will be used to determine the critical fluid dynamics and vessel parameters required for leukocyte adhesion. In this renewal, we also expand the scope to study the influence of flowing red and white blood cells on vascular biology and the formation of atherosclerotic lesions. As opposed to previous work, our approach includes implicitly the particulate nature of blood, and therefore more accurately reproduces the forces exerted in curved and branched vessels. A combination of in vivo experiments and mathematical modeling will be used to assess the combination of fluid forces and vessel geometries that lead to atherosclerotic lesions.
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