Role of Lung Microvascular Vasoactivity in Control of Lung Capillary Perfusion

肺微血管之间的血流分布被认为主要受微动脉收缩的控制。 和扩张术。然而，这种活性对微血管灌注性的影响尚不清楚。此外， 大量的解剖学证据表明，在肺微血管内进行主动灌流控制是可能的。 尽管这一课题从未被研究过。我们将在我们的理解中解决这些缺陷 使用我们开发的方法控制肺微血管。我们将确定起作用的血管活性物质 直接作用于肺微血管，而不是作用于肺小动脉或小静脉。我们还将 确定这些制剂如何影响红细胞微血管的灌注性。我们将在正常情况下进行这些研究 和缺氧性肺，以及在那些败血症损伤的患者中，确定这一对照的临床相关性。我们 提出以下具体目标： 1.肺微血管对产生全肺的药物的血管活性反应 血管收缩。我们将使用血管紧张素-II、缓激肽、5-羟色胺、血栓素对肺进行血管收缩 模拟U46619，或缺氧。特定直径(1.0、2.0、3.0或4.0？m)的乳胶颗粒将被注入 血管收缩过程中的每一个肺，然后肺将被迅速冻结。中的粒子密度 将在共聚焦组织学图像中测量每个直径(每个直径一个直径)颗粒的微血管 肺)。这些直径特定的颗粒密度将被用来量化在 各治疗组大鼠肺组织学观察。血管收缩药产生的微血管直径类似于 匹配流量控制将被认为主要影响小动脉。产生微血管的血管收缩药 直径小于匹配流量控制中的直径将被认为主要影响微血管。 产生比匹配血流对照更大的微血管直径的血管收缩药将 假定主要影响小静脉。这些结果将使我们能够识别每个血管节段 药剂主要收缩血管：在小动脉、微血管或小静脉。我们还将检查 低氧对正常和低氧大鼠的影响及Rho激酶和一氧化氮合酶的影响 进一步阐明每个血管节段的药理活性。这一目标的研究提供了 目标2和目标3的基线数据。 2.肺微血管红细胞对产生全肺的药物的灌流性反应 血管收缩。这一目标的研究量化了红细胞通过微血管的能力。 在目标1中使用的条件下。该目标的目标是确定 我们的目标是了解微血管直径的变化 在目标1中确定的转译为红细胞灌注性的相应变化。 3.肺微血管对已知可产生全肺的药物的血管活性反应 脓毒症所致肺部血管收缩。这一目标的目的是了解肺微血管直径如何 和反应性受到临床相关肺损伤的影响。肺毛细血管间的血流灌注分布 已知明显受到脓毒症的干扰，并导致通风/灌流异常。然而，败血症- 引起的微血管直径和血管反应性的改变也可能与此有关。这是一个 这是一个一无所知的课题，我们的研究将第一次解决这个问题。我们将使用乳胶 AIMS 1和2中使用的颗粒和红细胞方法来确定微血管直径和红细胞 脓毒症(内毒素输注)对灌注量的影响，以及如何确定药物的反应性 脓毒症会改变每段血管的长度。 我们的研究结果将扩大我们对肺微血管血流调节的基本认识。 这些药物可以改善肺损伤时的肺毛细血管灌注量。

Perfusion distribution among lung microvessels is thought to be controlled mainly by arteriolar constriction and dilation. However, effects of this activity on microvessel perfusability are unknown. Furthermore, considerable anatomic evidence suggests that active perfusion control is possible within the lung microvessels themselves, although this subject has never been studied. We will address these deficits in our understanding of pulmonary microvascular control using methods we developed. We will identify vasoactive agents that act directly on pulmonary microvessels versus those that act on pulmonary arterioles or venules. We will also determine how these agents affect red cell microvessel perfusability. We will conduct these studies in normal and hypoxic lungs, and in those injured by sepsis to determine the clinical relevance of this control. We propose the following specific aims: 1. Vasoactive response of lung microvessels to pharmacologic agents that produce whole-lung vasoconstriction. We will vasoconstrict lungs using angiotensin-II, bradykinin, serotonin, the thromboxane analog U46619, or hypoxia. Latex particles of a specific diameter (1.0, 2.0, 3.0, or 4.0 ¿m) will be infused into each lung during vasoconstriction and the lungs will then be rapidly frozen. Particle densities within the microvessels will be measured in confocal histological images for particles of each diameter (one diameter per lung). These diameter-specific particle densities will be used to quantify the average microvessel diameter in lungs of each treatment group. Vasoconstrictors that produce microvessel diameters similar to those in matched-flow controls will be assumed to affect mainly arterioles. Vasoconstrictors that produce microvessel diameters smaller than those in matched-flow controls will be assumed to affect mainly microvessels. Vasoconstrictors that produce microvessel diameters larger than those in matched-flow controls will be assumed to affect mainly venules. These results will allow us to identify the vascular segment in which each agent exerts the majority of its vasoconstriction: in arterioles, microvessels, or venules. We will also examine the effects of hypoxia, and the effects of Rho kinase and nitric oxide synthase (NOS), in normal and hypoxic lungs to further clarify the pharmacologic reactivity of each vascular segment. The studies in this aim provide the baseline data for aims 2 and 3. 2. Pulmonary microvessel red cell perfusability response to pharmacologic agents that produce whole-lung vasoconstriction. The studies in this Aim quantify the ability of red blood cells to flow through microvessels under the conditions utilized in Aim 1. The goals of this Aim are to determine the clinical relevance of the microvessel diameters identified in Aim 1. Our objective is to learn if the changes in microvessel diameters identified in Aim 1 translate to corresponding changes in the red cell perfusability. 3. Vasoactive response of lung microvessels to pharmacologic agents known to produce whole-lung vasoconstriction in lungs injured by sepsis. The goals of this aim are to learn how lung microvessel diameters and reactivity are affected by clinically relevant lung injury. Perfusion distribution among lung capillaries is known to be markedly disturbed by sepsis, and to cause ventilation/perfusion abnormalities. However, sepsis- induced changes in microvessel diameters and vasoreactivity may be responsible for this as well. This is a subject about which nothing is known, and our studies will address it for the first time. We will use the latex particle and red cell methods employed in Aims 1 and 2 to determine how microvessel diameters and red cell perfusion are affected by sepsis (LPS infusion), and to also determine how the pharmacologic responsiveness of each vessel segment is altered by sepsis. Results of our studies will expand our basic understanding of pulmonary microvascular flow regulation in normal and injured lungs, and lead to new treatments that improve lung capillary perfusion in lung injury.