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 是了解微血管通透性的生理调节， 营养物质输送到组织的重要决定因素。一氧化氮（NO）是一种 局部血流和血压的主要调节器;最近的研究支持其作用 NO在通透性调节中的作用。确定NO如何调节渗透性 这个实验室最近的数据使问题变得复杂， 传统的血管运输途径模型。数据显示，虽然 NO可改变血浆蛋白、白蛋白的流量和容积流量， 白蛋白可能通过对运动贡献很小的选择性途径产生 水和其他溶质。一种新的方法将被用来确定是否 选择性白蛋白转运发生在体内，基础上和刺激后， NO和下游信号分子环磷酸鸟苷（cGMP 表示否）。这些数据也支持NO可能与血液元素相互作用， 调节渗透性。三个目标将解决悬而未决的问题， NO调节通透性：1）哪些血管运输途径受到调节 NO和cGMP？我们假设NO和cGMP增强了容积和溶质通量 通过对流途径，而不影响选择性白蛋白转运。（二） 哪些细胞信号机制负责调节溶质 运输途径由NO？我们假设NO增强微血管 通过cGMP和cGMP依赖性蛋白作用的对流溶质通量 激酶。3)哪些血细胞与NO相互作用调节通透性？我们 假设中性粒细胞而不是血小板介导微血管 对NO的渗透性反应。 微血管通透性将有助于了解病理变化， 在诸如败血症、急性呼吸窘迫综合征、 和缺血再灌注损伤。长期目标是应用知识 从这些研究中获得，以使这些患者的最佳管理 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.