Inflammatory Mechanisms in Arterioles and Venules

小动脉和小静脉的炎症机制

• 批准号: 6922836
• 负责人: INGRID H SARELIUS
• 金额: $ 36.96万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922836
• 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）： 急性炎症的典型特征是微血管中的两种主要反应：1）白细胞-内皮细胞（EC）相互作用增加，最终导致白细胞从血管腔中移出; 2）微血管壁对溶质和水的渗透性增加，导致组织水肿。 神经元与血管壁的相互作用是炎症中发生的级联事件的核心，最终导致微血管屏障功能的改变，并与溶质渗透性变化的起始有关。 因此，本申请中提出的研究的总体目标是检验以下一般假设，即小动脉和小静脉中的炎症反应的基础机制是根本不同的，无论是关于白细胞在调节溶质渗透性变化中的作用，以及关于血管屏障功能的这两个关键方面是否具有基本的共同信号传导机制（特别是那些依赖于Ca 2+的）。 一般目标将在啮齿类动物骨骼肌的完整小动脉和小静脉中实现，通过进行以下目标。 我们将使用直接测量的白细胞-EC相互作用，渗透性和EC Ca 2+的变化，在完整的，自动灌注原位啮齿动物（小鼠，大鼠）骨骼肌小动脉和小静脉，以确定中性粒细胞激活的渗透性变化的机制，并确定这些不同的小动脉与小静脉。 假设1：ICAM-1连接足以增加溶质渗透性并诱导小动脉和小静脉中的白细胞渗出。 假设1A：微血管对溶质和白细胞的渗透性可以通过从嗜中性粒细胞释放的旁分泌产物（CAP 37）而增加超过由于单独的ICAM-1连接所致的渗透性。 假设2：EC Ca 2+的增加足以增加溶质渗透性并诱导小动脉和小静脉中的白细胞渗出。 假设2A：选择素和ICAM-1连接均与EC Ca 2+增加和通透性增加相关。 在相同条件下对两种骨骼肌微血管的研究将使在单一的、定义明确的完整血管模型中确定屏障功能调节的主要机制和重要的一般原则成为可能。 了解微血管屏障功能的调节机制，以及它们在小动脉和小静脉系统之间的潜在变化，对于了解炎症性疾病的进展具有直接相关性。