MECHANISM OF HUMAN TRANSENDOTHELIAL LEUKOCYTE MIGRATION

人类跨内皮白细胞迁移机制

• 批准号: 6056276
• 负责人: SAMUEL CHARLES SILVERSTEIN
• 金额: $ 28.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6056276
• 关键词: calcium flux; cell migration; chemoattractants; human tissue; intercellular connection; monocyte; myosin light chain kinase; myosins; phosphoproteins; phosphorylation; tissue /cell culture; vascular endothelium; vascular endothelium permeability

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.

炎症在许多疾病的发病机制中起着重要作用 包括动脉粥样硬化、免疫复合物介导的反应和长期 许多感染的长期后遗症。 白细胞跨血管迁移 内皮细胞是炎症反应的关键步骤。 虽然很多是 已知白细胞粘附到 EC，白细胞粘附的机制 EC之间的连接点打开情况未知。 受刺激的 PMN 信号 EC 胞质游离钙浓度增加。 EC 的这种增加 (Ca++ (i) 调节跨内皮迁移表明模拟 PMN 产生细胞外物质。 单核细胞和人单核细胞 THP-1 系也会引发 EC *(Ca+++(i) 的增加，从而调节 单核细胞跨内皮迁移。 这些发现构成了基础 白细胞发出 EC 之间连接打开的信号的假设 为了跨越 EC 屏障迁移。 可以从以下几个方面 将研究假设：1）。 识别/表征物质 通过刺激 PMN 增加 EC（(Ca++(i)，EC 磷酸化 MLC、EC 的渗透性 MLC、EC 的渗透性 巨细胞决定了该产品的生物学特性 3)。 确定 EC 蛋白激酶（例如 MLC 激酶）在药物治疗中的作用 白细胞跨 EC 单层迁移。 体外培养系统 人羊膜上的 EC 和测量 EC 的方法 ((Ca++(i), EC 单核细胞对离子的通透性、EC MLC 磷酸化和白细胞 跨 EC 单层的迁移将用于进行这些研究。 这 本申请中提出的研究应有助于理解 白细胞穿过 EC 屏障迁移的机制 其中EC调节血管通透性。 对这些的了解 流程很好地为制定合理的战略提供了基础 预防/治疗以炎症为特征的疾病。