Lung Perfusion Heterogeneity and Mechanisms of Edema

该建议旨在了解肺血流分布的空间异质性， 增加的肺毛细血管压力相互作用以影响肺水肿的发展。高 高原肺水肿（HAPE），一种急性潜在致命性水肿被用作疾病模型，以允许 研究肺水肿的机制，无混杂变量，如脓毒症或多 器官衰竭肺毛细血管的机械应力损伤已被证明是重要的， HAPE的发展，但肺毛细血管如何暴露于高压尚未解决。的 这一建议的总体假设是，增加对HAPE的易感性需要缺氧诱导的 灌注不均匀性增加和肺血管压力增加，导致肺水肿。 肺区域的流量和压力增加。使用定量功能磁共振成像 （fMRI）技术称为动脉自旋标记（ASL），我们以前已经表明，区域肺 在HAPE中，在常压缺氧期间，血流在单个等重力平面上变得不均匀 在HAPE耐药受试者中未观察到的发现支持了这一观点。的 低氧和运动对肺血流空间分布的影响将在 使用最新技术水平的定量fMRI-ASL，在海平面下的整个肺，以及与增加相关的变化 采用非对比多回波MRI技术测量局部血管外液体。这将允许洞察力 进入水肿的机制，因为如果不均匀缺氧肺血管收缩是前毛细血管 收缩，则高毛细管压力（和流体积聚）将发生在高流量（较少）中。 收缩的）区域，由于小动脉阻力低而暴露于高肺动脉压力。一 在低流量的肺区域中发现水肿将相反地暗示毛细血管后静脉收缩。的 将评价肺血管反应的解剖学再现性，以确定 缺氧时的灌注变化模式在区域上是稳定的，或者高流量区域是否发生变化， 它们的解剖位置。如果它们是区域性的，这将表明， 某些肺部区域的固有结构异常，而解剖学上可变的反应将 表明一个主要是动态的相互依存的过程。最后是适应环境的影响， 运动（HAPE的重要调节因素）对灌注异质性增加的影响 并将评估由此产生的流体积聚。这些研究的结果可能会提供一些见解， 当肺血管中的压力降低时， 增加和减少可用的氧气。特别是，通过评估血液之间的关系 流动和液体形成的肺，这项工作可能允许确定一个阈值肺损伤下 确定某些条件和预测那些谁是在肺水肿的风险。

This proposal seeks to understand how spatial heterogeneity in the distribution of pulmonary blood flow and increased pulmonary capillary pressures interact to affect the development of pulmonary edema. High altitude pulmonary edema (HAPE), an acute potentially fatal edema is used as a disease model, to allow investigation of mechanisms of pulmonary edema without confounding variables such as sepsis or multi- organ failure. Mechanical stress injury of the pulmonary capillaries has been shown to be important in the development of HAPE, but how the pulmonary capillaries are exposed to high pressure is unresolved. The overall hypothesis of this proposal is that increased susceptibility to HAPE requires both a hypoxia-induced increase in perfusion heterogeneity and increased pulmonary vascular pressures, resulting in edema in the lung regions of increased flow and pressure. Using a quantitative functional magnetic resonance imaging (fMRI) technique known as arterial spin labeling (ASL) we have previously shown that regional pulmonary blood flow becomes less uniform in a single isogravitational plane during normobaric hypoxia in HAPE suceptible subjects, a finding which is not observed in HAPE resistant subjects, supporting this idea. The effects of hypoxia and exercise on the spatial distribution of pulmonary blood flow will be measured in the entire lung at sea level, using state of the art quantitative fMRI-ASL, and changes related to increased regional extravascular fluid measured with a non-contrast multi echo MR I technique. This will allow insights into the mechanism of the edema, since if the uneven hypoxic pulmonary vasoconstriction is pre-capillary constriction, then the high capillary pressures (and fluid accumulation) will occur in the high flow (less constricted) regions, exposed to the high pulmonary artery pressure due to low arteriolar resistance. A finding of edema in lung regions of low flow would conversely implicate post capillary venoconstriction. The anatomic reproducibility of the pulmonary vascular response will be evaluated to determine whether the pattern of perfusion changes with hypoxia are regionally stable, or whether the regions of high flow change their anatomic location over time. If they are regionally reproducible, this would suggest that there are inherent structural abnormalities in some lung regions, while an anatomically variable response would suggest a predominantly dynamic interdependent process. Finally the effects of acclimatization, and exercise (important modulating factors for HAPE) on the development of increased perfusion heterogeneity and resultant fluid accumulation will be evaluated. The results of these studies may offer insights into how fluid accumulates in the lung under conditions of stress when the pressure in the lung blood vessels is increased and available oxygen is reduced. In particular, by evaluating the the relationship between blood flow and fluid formation in the lung, this work may allow the identification of a threshold for lung injury under certain conditions to be identified and the prediction of those who are at risk for pulmonary edema.