Blood rheology, cell adhesion and endothelial activation

描述(由申请人提供)： 红细胞(RBC)通过赋予血液独特的悬浮神学，在白细胞-内皮细胞(L-E)的相互作用中发挥重要作用。例如，我们之前发现，当流室中细胞悬浮液的红细胞压积从0增加到30%时，结合的白细胞数量增加了10倍。红细胞存在时细胞粘附力的增强是由于流动的淋巴细胞和红细胞之间的物理作用，而不是生化作用。在这笔赠款的前三年，我们已经展示了血细胞之间的机械相互作用如何促进白细胞滚动和粘连。我们首次估计了流动的血液中施加的流体动力，当细胞进入毛细血管后小静脉并在内皮上滚动时，这些流体动力会影响细胞。这些研究提供了对白细胞滚动机制的更好的理解，并表明血管几何形状和红细胞结构在白细胞在毛细血管后小静脉滚动中起着重要作用。正如在最初的申请中提出的，我们已经证明了将WBC推到墙边所需的红细胞的最佳配置。在这一竞争更新中，我们扩展了这些研究，通过检测体内不同组织中的白细胞滚动，来研究血管形状和红细胞聚集在启动白细胞滚动中的作用。将使用数学建模和新颖的微制造网络来确定白细胞黏附所需的关键流体动力学和血管参数。在这次更新中，我们还扩大了研究红细胞和白细胞流动对血管生物学和动脉粥样硬化病变形成的影响的范围。与以前的工作不同，我们的方法隐含地包括了血液的颗粒性质，因此更准确地再现了弯曲和分支血管中施加的力。体内实验和数学模型的结合将被用来评估导致动脉粥样硬化损害的流体作用力和血管几何形状的组合。

DESCRIPTION (provided by applicant): 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.