Regulation of microvascular permeability by nitric oxide

描述(由申请人提供)：本研究计划的总体目标 是为了了解微血管通透性的生理调节，以及 营养物质向组织输送的重要决定因素。一氧化氮(NO)是一种 局部血流和血压的主要调节器；最近的研究支持了 NO在通透性调节中的作用。确定NO如何调节通透性 最近来自这个实验室的数据使情况变得复杂起来，这些数据挑战了 血管运输途径的传统模型。数据显示，虽然 NO可以改变血容量和血清蛋白、白蛋白、血清白蛋白转运的流量 白蛋白可能通过对运动贡献很小的选择性途径发生。 水和其他溶质。将使用一种新的方法来确定 白蛋白的选择性转运在体内、基础上和在刺激下发生 NO和环鸟苷一磷酸(CGMP)，一种下游信号分子 表示不)。数据还支持一氧化氮可能与血液中的元素相互作用。 通透性调节。三个目标将解决尚未解决的问题，即如何 NO调节通透性：1)调节哪些血管运输途径 NO和cGMP？我们假设NO和cGMP增加了体积和溶质通量 通过对流路径，不影响白蛋白的选择性运输。2) 哪些细胞信号机制负责调节溶质 运输路径由否？我们假设一氧化氮增强了微血管 作用于cGMP及其依赖蛋白的对流溶质通量 激活剂。3)在通透性调节中，哪些血细胞与NO相互作用？我们 假设中性粒细胞，而不是血小板，调节微血管 渗透性对NO的响应。更广泛的生理调节知识 微血管通透性将有助于了解血管的病理改变 脓毒症、急性呼吸窘迫综合征等情况下的通透性 和缺血再灌注损伤。我们的长期目标是应用这些知识 从这些研究中获得，以实现对患有这些疾病的患者的最佳管理 重要的临床实体及其相关的微血管改变。

DESCRIPTION (provided by applicant): The overall goal of this research program is to understand physiologic regulation of microvascular permeability, an important determinant of nutrient delivery to tissues. Nitric oxide (NO) is a major regulator of local blood flow and pressure; recent studies support a role of NO in regulation of permeability. Determining how NO regulates permeability is complicated by recent data from this laboratory that challenge the traditional models of vascular transport pathways. The data reveal that while NO can modify flux of volume and of the serum protein, albumin, transport of albumin may occur through selective pathways that contribute little to movement of water and other solutes. A novel approach will be used to determine whether selective albumin transport occurs in vivo, basally and upon stimulation with NO and cyclic guanosine monophosphate (cGMP, a downstream signaling molecule for NO). The data also support that NO may interact with blood elements in regulation of permeability. Three aims will address unresolved questions of how NO regulates permeability: 1) Which vascular transport pathways are regulated by NO and cGMP? We hypothesize that NO and cGMP enhance volume and solute flux through convective pathways, without affecting selective albumin transport. 2) Which cell signaling mechanisms are responsible for regulation of solute transport pathways by NO? We hypothesize that NO enhances microvascular convective solute flux by acting through cGMP and cGMP-dependent protein kinase. 3) Which blood cells interact with NO in regulation of permeability? We hypothesize that neutrophils, and not platelets, mediate microvascular permeability responses to NO. Broader knowledge of physiologic regulation of microvascular permeability will help understand pathologic alterations in permeability in conditions such as sepsis, acute respiratory distress syndrome and ischemia-reperfusion injury. The long-term goal is to apply the knowledge gained from these studies to allow optimal management of patients with these important clinical entities and their associated microvascular alterations.