Lung Perfusion Heterogeneity and Mechanisms of Edema

描述（由申请人提供）：本提案旨在了解肺血流分布的空间异质性和肺毛细血管压力增加如何相互作用影响肺水肿的发展。高原肺水肿（HAPE）是一种急性可能致命的水肿，被用作疾病模型，允许研究肺水肿的机制，而没有混淆变量，如败血症或多器官衰竭。肺毛细血管的机械应力损伤已被证明在HAPE的发展中很重要，但肺毛细血管如何暴露于高压尚不清楚。该建议的总体假设是，HAPE易感性的增加需要缺氧诱导的灌注异质性的增加和肺血管压力的增加，从而导致肺流量和压力增加区域的水肿。使用定量功能磁共振成像（fMRI）技术，即动脉自旋标记（ASL），我们之前已经表明，在HAPE易感受试者的常压缺氧期间，局部肺血流在单个等重力平面上变得不均匀，这一发现在HAPE抗性受试者中没有观察到，支持了这一观点。缺氧和运动对肺血流空间分布的影响将使用最先进的定量fMRI-ASL在海平面上测量整个肺，并使用非对比多回声MRI技术测量与区域血管外液体增加相关的变化。这将有助于深入了解水肿的机制，因为如果不均匀的缺氧肺血管收缩是毛细血管前收缩，那么毛细血管高压（和液体积聚）将发生在高流量（收缩较少）区域，由于小动脉阻力低而暴露于肺动脉高压。在低流量肺区发现水肿反过来暗示毛细血管后静脉收缩。将评估肺血管反应的解剖再现性，以确定缺氧时灌注变化的模式是否在局部稳定，或者高血流区域是否随时间改变其解剖位置。如果它们是区域可重复的，这将表明在某些肺区域存在固有的结构异常，而解剖学上可变的反应将表明一个主要的动态相互依赖的过程。最后，将评估环境适应和运动（HAPE的重要调节因素）对灌注异质性增加和由此产生的液体积聚的影响。这些研究的结果可能会让我们深入了解，当肺部血管压力增加、可用氧气减少时，肺中的液体是如何在应激条件下积聚的。特别是，通过评估肺血流和液体形成之间的关系，这项工作可以确定在某些条件下肺损伤的阈值，并预测哪些人有肺水肿的风险。

DESCRIPTION (provided by applicant): 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 susceptible 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 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.