Lung Perfusion Heterogeneity and Mechanisms of Edema

这一建议试图理解肺血流分布的空间异质性如何 肺毛细血管压力升高相互作用，影响肺水肿的发展。高 高原肺水肿(HAPE)，一种急性的潜在致命的水肿，被用作疾病模型，以允许 无脓毒症或多发性肺炎等混杂变量的肺水肿机制探讨 器官衰竭。肺毛细血管的机械性应力损伤已被证明在 HAPE的发展，但肺毛细血管如何暴露在高压下仍未解决。这个 这一建议的总体假设是，增加对HAPE的易感性需要低氧诱导的 血流灌注的不均一性和肺血管压力的增加，导致 肺内血流和压力增加的区域。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，区域性肺 高原常压低氧时，单个等重面的血流变得不均匀 成功的受试者，这一发现在抗肺气管炎的受试者中没有观察到，支持这一观点。这个 低氧和运动对肺血流空间分布的影响将在 全肺在海平面，使用最先进的定量fMRI-ASL，以及与增加相关的变化 用非对比多回波磁共振成像技术测量局部血管外液体。这将使人们能够洞察 探讨水肿的机制，因为如果不均匀的缺氧性肺血管收缩是毛细血管前 收缩，则在高流量(少)时会出现高毛细管压力(和流体聚集) 狭窄)区域，暴露于低小动脉阻力所致的高肺动脉压。一个 在低血流的肺区发现水肿会反过来暗示毛细血管后静脉收缩。这个 将评估肺血管反应的解剖学重复性，以确定是否 低氧时血流灌注改变的模式是区域性稳定的，或者高血流区域是否改变 随着时间的推移它们的解剖位置。如果它们在区域上是可复制的，这将表明有 一些肺部区域的固有结构异常，而解剖学上的可变反应 暗示了一个主要的动态的相互依赖的过程。最后，驯化的影响，以及 运动(HAPE的重要调节因素)对血流灌注异质性增加的影响 并对由此产生的流体堆积进行评估。这些研究的结果可能会为我们提供关于 在压力条件下，当肺血管的压力是 有效氧增加，有效氧减少。特别是，通过评估血液与血液之间的关系 在肺中的流动和液体形成，这项工作可能允许识别肺损伤的阈值 需要确定的某些情况以及那些有肺水肿风险的人的预测。

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.