Inflammatory Mechanisms in Arterioles and Venules

小动脉和小静脉的炎症机制

• 批准号: 7099551
• 负责人: INGRID H SARELIUS
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099551
• 关键词: arterioles; biological signal transduction; calcium flux; capillary; cell adhesion; cell adhesion molecules; cell cell interaction; inflammation; laboratory mouse; laboratory rat; leukocytes; microcirculation; neutrophil; selectins; striated muscles; vascular endothelium; vascular endothelium permeability

DESCRIPTION (provided by applicant): Acute inflammation is typified by two principal responses in microvessels: 1) an increase in leukocyte-endothelial cell (EC) interactions culminating in leukocyte emigration from the vascular lumen; and 2) increased permeability of the microvascular wall to solutes and water, resulting in tissue edema. Neutrophil interactions with the vessel wall are central to the cascade of events that occurs in inflammation to ultimately result in the alteration in microvascular barrier function, and have been implicated in initiation of solute permeability changes. The overall goal of the studies proposed in this application is therefore to test the general hypothesis that mechanisms underlying inflammatory responses in arterioles and venules are fundamentally different, both with respect to the role of leukocytes in regulation of solute permeability changes, and with respect to whether these two critical aspects of vascular barrier function share essential common signaling mechanisms (specifically those that are Ca2+ dependent). The general goal will be approached in intact arterioles and venules of rodent skeletal muscle, by undertaking the following aims. We will use direct measurements of leukocyte-EC interactions, permeability and EC Ca2+ changes in intact, autoperfused in situ rodent (mice, rats) skeletal muscle arterioles and venules, to define the mechanisms for neutrophil activation of permeability changes, and determine how these differ in arterioles vs. venules. Hypothesis 1: ICAM-1 ligation is sufficient to increase solute permeability and to induce leukocyte diapedesis in both arterioles and venules. Hypothesis 1A: Microvessel permeability to solutes and leukocytes can be increased above that due to ICAM-1 ligation alone by a paracrine product (CAP37) release from neutrophils. Hypothesis 2: An increase in EC Ca2+ is sufficient to increase solute permeability and to induce leukocyte diapedesis in both arterioles and venules. Hypothesis 2A: Both Selectin and ICAM-1 ligation are associated with increased EC Ca2+ and with increased permeability. The study of both skeletal muscle microvasculatures under the same conditions will enable the major mechanisms and important general principles governing regulation of barrier function to be identified in a single, well defined intact vessel model. Understanding mechanisms for regulation of microvascular barrier function, and their potential variation between arteriolar and venular system is of immediate relevance to understanding the progress of inflammatory diseases.

描述（由申请人提供）： 急性炎症是微血管中的两个主要反应：1）白细胞 - 内皮细胞（EC）相互作用的增加，最终从血管腔中的白细胞移民中迁移； 2）微血管壁对溶质和水的渗透性增加，导致组织水肿。 与血管壁相互作用是炎症中发生的一系列事件的核心，最终导致微血管屏障功能的改变，并且与溶质渗透性变化有关。 因此，在本应用中提出的研究的总体目标是检验一个总体假设，即动脉和静脉的炎症反应的基础机制在根本上是不同的，这在白细胞在调节溶质渗透性变化中的作用方面都是不同的，而对于这些关键方面的依赖性的两个关键方面是普遍的，这些方面是普遍的（特异性的）。 通过实现以下目标，将在完整的动脉和啮齿动物骨骼肌的静脉中实现总体目标。 我们将直接测量白细胞-EC相互作用，渗透率和EC CA2+完整的EC CA2+变化，自动捕获的原位啮齿动物​​（小鼠，老鼠）骨骼肌动脉和静脉静脉，定义了中性粒细胞粒细胞渗透性变化的机制，并确定这些与Arterioles Vs. Venter venter venter venter venter venter venter的机制。 假设1：ICAM-1连接足以增加溶质的渗透性并诱导小动脉和静脉内的白细胞尿布。 假设1a：微血管对溶质和白细胞的渗透性可以增加，而高于单独的ICAM-1与旁分泌产物（CAP37）从中性粒细胞中释放出来。 假设2：EC Ca2+的增加足以增加溶质的渗透性并诱导小动脉和静脉曲张中的白细胞尿。 假设2a：选择素和ICAM-1结扎均与EC Ca2+的增加以及渗透率增加有关。 在相同条件下对两种骨骼肌微血管的研究将使屏障功能调节的主要机制和重要的一般原则可以在单个，明确的完整容器模型中识别。 了解调节微血管屏障功能的机制及其在小动脉和静脉系统之间的潜在变化与了解炎症性疾病的进展是直接相关的。