Control of leukocyte emigration in reperfused myocardium

项目3：再灌注心肌中白细胞迁移的控制项目3的长期目标集中在中性粒细胞和单核细胞迁移到炎症部位并与实质细胞相互作用的机制上。该项目开发了许多体外实验模型，用于鉴定可能在再灌注心肌中起作用的机制。这些特异的粘附分子，以及在局部细胞因子和趋化因子的作用下发生的功能变化。这个项目有两个具体目标，每个目标下都有直接和集中的子目标，这些子目标与已知存在于再灌注心肌中的条件或因素有关。它们被选择来填补我们对控制白细胞迁移和心脏功能机制的理解空白。明确再灌注心肌中白细胞粘附和信号级联操作的新步骤。这一目标的具体重点将放在四个领域；A)在血流剪切条件下将白细胞粘附在内皮细胞上的粘附分子选择素家族诱导白细胞功能的改变；b) CD18整合素家族成员LFA-1在中性粒细胞中的广泛功能；c)心肌ICAM-1 （CD18整合素的配体）支持的白细胞功能与外周小静脉的ICAM-1相比；d)心肌中抑癌素M和IL-15在粘附和信号级联中的功能贡献。明确再灌注心肌中调节白细胞粘附和信号级联的抗粘附机制。这一目标的具体重点将放在三个领域；a)以IL-1和IL-4为模型的细胞因子联合刺激的抗粘附性能；b)心肌再灌注后抗炎细胞因子上调的潜在作用，重点是IL-10；c)可溶性心肌粘附分子，特别是ICAM-1的潜在贡献。

PROJECT 3: Control of Leukocyte Emigration in Reperfused Myocardium Project 3 focuses its long term objective on the mechanisms by which neutrophils and monocytes emigrate into inflammatory sites and interact with parenchymal cells. The project has developed a number of in vitro experimental models of identification The project has developed The project has developed a number of in vitro experimental models for identification of mechanisms that may operate in the reperfused myocardium. These specific adhesion molecules, and the changes in functions that occur in response to local cytokines and chemokines. This general approach will continue in the present application There are two specific aims for this project with immediate and focused sub-aims under each that are linked to condition or factors known to be present in the reperfused myocardium. They are chosen to fill gaps in our understanding of the mechanisms that control leukocyte emigration and function in the heart. Specific Aim 1- Define new steps in the leukocyte adhesion and signaling cascade operate in reperfused myocardium. The specific focus of this aim will be in four areas; a) alterations in leukocyte functions induced by the selectin family of adhesion molecules that tether leukocytes to endothelial cells under conditions of shear by flowing blood; b) the broad functions in neutrophils of LFA-1, a member of the CD18 integrin family; c) the leukocyte functions supported by myocardial ICAM-1 (a ligand for CD18 integrins) in contrast to ICAM-1 on peripheral venules; and d) the functional contributions of oncostatin M and IL-15 in myocardium as they apply to the adhesion and signaling cascade. Specific Aim 2- Define anti-adhesive mechanisms that modulate the leukocyte adhesion and signaling cascade in reperfused myocardium. The specific focus of this aim will be in 3 areas; a) the anti-adhesive properties of combined cytokine stimulation using IL-1 and IL-4 as a model; b) the potential role of anti-inflammatory cytokines up-regulated in the myocardium by reperfusion, with focus on IL-10; and c) the potential contributions of soluble myocardial-derived adhesion molecules, especially ICAM-1.