Integrins and Inflammation in the Vessel Wall

炎症是心血管疾病的主要独立危险因素。其中一个突出的 与这些疾病相关的特征是血管内存在大量巨噬细胞。 损伤，通过启动和维持炎症和 血栓形成和随后的纤维斑块破裂。在上一次筹资期间， 我们研究了炎症环境中激活的巨噬细胞的迁移，并确定了Mac-1， TPA、纤维蛋白、PAI-1和LRP在这一过程中起重要作用。基于这些结果，我们假设 这一应用使巨噬细胞在炎症环境中高效迁移，其功能 在急性炎症的消退和血管病变的进展过程中，依赖于 三个生理上突出的系统(整合素、凝血和内吞)的协同作用。我们 认为炎症或血管损伤会导致富含纤维蛋白的基质的形成。当被激活时， 巨噬细胞附着在与丝氨酸蛋白酶tPA复合的临时基质纤维蛋白上。 随后，tPA被其特定的抑制剂PAI-1中和，PAI-1进而增强整合素蛋白酶-1的结合。 内吞受体LRP的抑制剂复合体，从而触发从细胞黏附到 细胞分离，促进受体内化。然后，内化的受体被循环到 细胞表面和下一周期的黏附、脱离和受体内化再次开始。是这样的 细胞迁移的各个步骤之间在空间和时间上的有序转换导致高效 巨噬细胞迁移。我们计划使用一组缺陷小鼠来验证这一假设，其中包括Mac-1， 纤维蛋白原、tPA、PAI-1和LRP。我们还将产生Mac-1、tPA、PAI-1和LRP的特定突变体 无法与各自的合作伙伴交互，因此将不支持 以上蛋白复合体或巨噬细胞迁移。从这个项目中获得的信息将提供 炎症环境中巨噬细胞迁移的详细机制洞察，可能有助于我们更好地 了解以下两种情况下调节急性炎症的分子事件 病理情况下血管壁内血管病变的生理条件或发展 设置。

Inflammation represents a major independent risk factor for cardiovascular diseases. One of the prominent features associated with these diseases is the presence of abundant macrophages within the vascular lesions, which contribute to disease development by initiating and sustaining both inflammation and thrombosis and by causing subsequent rupture of the fibrous plaques. During the previous funding period, we studied migration of activated macrophages within an inflammatory environment and identified Mac-1, tPA, fibrin, PAI-1, and LRP as important players in this process. Based on these results, we hypothesize in this application that efficient macrophage migration within inflammatory environments, which functions critically in the resolution of acute inflammation and also during the progression of vascular lesions, depends on cooperation of three physiologically prominent systems (integrins, coagulation, and endocytosis). We propose that inflammation or vascular injury results in the formation of a fibrin-rich matrix. When activated, macrophages adhere to the provisional matrix fibrin that is complexed with the serine protease tPA. Subsequently, tPA is neutralized by its specific inhibitor PAI-1, which in turn enhances binding of the integrinprotease- inhibitor complex to the endocytic receptor LRP, and thus triggers a switch from cell adhesion to cell detachment and promotes receptor internalization. The internalized receptors are then recycled to the cell surface and the next cycle of adhesion, detachment and receptor internalization starts again. Such orderly transitions both spatially and temporally among the individual steps of cell migration lead to efficient macrophage migration. We plan to test this hypothesis using a panel of deficient mice, including Mac-1, fibrinogen, tPA, PAI-1, and LRP. We will also generate specific mutants of Mac-1, tPA, PAI-1, and LRP that are unable to interact with their respective partners and thus will not support the sequential assembly of the above protein complex or macrophage migration. The information obtained from this project will provide detailed mechanistic insights in macrophage migration within an inflammatory milieu and may help us better understand the molecular events that regulate either proper resolution of an acute inflammation under physiological conditions or the development of vascualr lesions within the vessel wall under pathological settings.