MECHANISM OF HUMAN TRANSENDOTHELIAL LEUKOCYTE MIGRATION

炎症在许多疾病的发病机制中起主要作用。 包括动脉粥样硬化、免疫复合物介导的反应和长时间的 许多感染的长期后遗症。白细胞在血管内的迁移 内皮细胞是炎症反应中的关键步骤。虽然很多都是 已知白细胞与内皮细胞的黏附，白细胞 打开EC之间的连接点是未知的。受激PMN信号AN EC胞浆游离钙浓度升高。欧共体的这种增长 (Ca++(I)调节跨内皮细胞迁移表明模拟PMN 产生一种胞外物质。单核细胞和人类单核细胞 品系THP-1也启动了EC*(Ca++(I))的增加，它调节 单核细胞跨内皮细胞迁移。这些发现构成了以下结论的基础 假设白细胞是EC之间连接开放的信号 为了跨越欧共体的障碍。的以下几个方面 将研究的假设：1)。确定/表征物质(S) 通过刺激中性粒细胞S，使EC((Ca++(I))，EC的磷酸化 MLC，EC MLC的渗透性，EC的渗透性 巨噬细胞确立了该产品的生物学特性。 确定EC蛋白激酶，如MLC激酶，在药物治疗中的作用 白细胞在EC单层间的迁移。一种体外培养系统 人羊膜上的EC及其测定方法((Ca++(I)，EC 单核细胞对离子的通透性、EC MLC磷酸化与白细胞 跨越EC单层的迁移将用于执行这些研究。这个 本申请书中提出的研究应有助于理解 白细胞跨过EC屏障和通过 其中EC调节血管通透性。对这些的理解 过程很好地为AAT开发合理的策略提供了基础 以炎症为特征的疾病的预防/治疗。

Inflammation plays a major role in the pathogenesis of many diseases including atherosclerosis, immune complex-mediated responses and the long term sequelae of many infections. Leukocyte migration across the vascular endothelium is a critical step in an inflammatory response. While much is known about leukocyte adhesion to EC, the mechanism by which leukocytes open the junctions between EC is unknown. Stimulated PMN signal an increase in EC cytosolic free calcium concentrations. Such increases in EC (Ca++ (i) regulate transendothelial migration indicated that simulated PMN produce an extracellular substance. Monocytes and a human monocytic cell line, THP-1, also initiate increases in EC *(Ca+++(i) which regulates transendothelial monocyte migration. These findings form the basis for the hypothesis that leukocytes signal the opening of junctions between EC in order to migrate across EC barrier. The following aspects of the hypothesis will be studied: 1). identify/characterize the substance (s) by stimulated PMN s that increase in EC ((Ca++(i), phosphorylation of EC MLC, and the permeability of EC MLC, and the permeability of EC megalocytes establish the biological properties of this product 3). determine the role of EC protein kinases, such as MLC kinase, in medicating leukocyte migration across EC monolayers. An in vitro system of culturing EC on human amniotic membranes and methods for measuring EC ((Ca++(i), EC monocyte permeability to ions, EC MLC phosphorylation and leukocyte migration across EC monolayers will be used to perform these studies. The studies proposed in this application should contribute to an understanding of the mechanisms by which leukocytes migrate across EC barriers and by which EC regulate vascular permeability. An understanding of these processes well provide a basis for developing rational strategies for athe prevention/treatment of diseases characterized by inflammation.