Pulmonary Microcirculatory Hemodynamics

描述(申请人提供)：新的证据表明，肺循环在动脉和毛细血管内都有意想不到的调节形式。我们实验室的肺微血管系统的视频显微镜显示，并不是所有的毛细血管都是持续灌流的；相反，血流在毛细血管之间不断地切换。即使在血管压力和流量不变的情况下，这种转换也会继续。这种转换不是随机的：它遵循一种微妙的、重复的模式，本质上是分形的，取决于每个牙槽网络的独特特征。这导致了邻近肺泡之间独立的灌流模式，创建了一个健壮的系统，其中一个网络的故障不会影响邻居。具体目标1.确定导致单个毛细血管网络中毛细血管之间的流量切换的机制。这种转换可能是颗粒流体流经复杂但被动的毛细血管网络的结果，也可能是由活跃的毛细血管运动引起的。为了区分这些原因，我们将使用我们开发的软件来分析灌流模式，并使用分形数学来确定灌流模式的重复程度。我们的第一个假设是，毛细血管是被动的；毛细血管之间的血流切换是高度灵活的红细胞穿过组成网络的数十个毛细血管连接的结果。第二个假设是毛细血管是活跃的；毛细血管之间的血流切换是由毛细血管管腔直径的活跃变化决定的。我们将通过创造一种被动状态来检验这些假说，在被动状态下，毛细血管的管腔直径是固定的，从而阻止毛细血管改变其管腔的能力。未更改的切换将表明网络是被动的。改变的开关将是毛细血管运动的直接证据。在特定的目标2中，我们将研究支配肺动脉的交感神经的功能。刺激星状交感神经节可使肺动脉壁变硬，从而增加肺动脉收缩压。我们假设，当增强的收缩压波到达毛细血管床时，气体交换表面积将通过毛细血管的募集而增加。我们的试点数据有力地表明，这一假设是正确的。我们将通过研究交感神经刺激期间毛细血管灌流的变化来完成对这一假设的广泛测试。这些实验的成功完成将用一种新的概念取代目前认为肺循环不太起作用的想法，即这些血管能够有效而微妙地控制。经过几十年的技术发展，我们终于能够进行这些实验了。

DESCRIPTION (provided by applicant): New evidence suggests that the pulmonary circulation has unexpected forms of regulation, both in the arteries and within capillaries. Videomicroscopy of the pulmonary microvasculature in our laboratory shows that not all capillaries are continually perfused; rather the blood flow continually switches among the capillaries. The switching continues even when vascular pressures and flows are constant. The switching is not random: it follows a subtle, repeating pattern that is fractal in nature and depends on the unique characteristics of each alveolar network. This results in perfusion patterns that are independent among neighboring alveoli, creating a robust system in which failure of one network does not affect the neighbors. Specific Aim 1. To determine the mechanisms that cause the switching of flow among capillaries in individual capillary networks. The switching could be the result of a particulate fluid flowing through a complex but passive capillary network, or it could be caused by active capillary vasomotion. To differentiate between these causes, we will analyze the perfusion patterns using software we have developed, as well as fractal mathematics to determine the level of repetition of the perfusion patterns. Our first hypothesis is that the capillaries are passive; the switching of blood flow among the capillaries is the result of highly flexible red blood cells traversing dozens of capillary junctions that comprise the network. The second hypothesis is that the capillaries are active; switching of blood flow among the capillaries is determined by active changes of capillary lumenal diameter. We will test these hypotheses by creating a passive state in which the capillary lumenal, diameters are fixed, thereby blocking the ability of the capillaries to alter their lumens. Unaltered switching would show that the network was passive. Altered switching would be direct evidence for capillary vasomotion. In Specific Aim 2 we will investigate the function of the sympathetic nerves that innervate the pulmonary arteries. Stimulation of the stellate sympathetic ganglion stiffens the pulmonary arterial walls, which increases pulmonary arterial systolic pressure. We hypothesize that when the enhanced systolic pressure wave reaches the capillary bed, the gas exchange surface area will increase through the recruitment of capillaries. Our pilot data strongly suggests this hypothesis is correct. We will complete an extensive test of this hypothesis by studying the changes in capillary perfusion during sympathetic stimulation. Successful completion of these experiments will replace the current idea, that the pulmonary circulation does not do very much, with a new concept that these vessels are capable of potent yet subtle control. After decades of technical development, we are at last in a position to conduct these experiments.