Lung Perfusion Heterogeneity and Mechanisms of Edema

肺灌注异质性和水肿机制

• 批准号: 7102554
• 负责人: Susan R Hopkins
• 金额: $ 38.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102554
• 关键词: acclimatization; adolescence (12-20); altitude; capillary; clinical research; disease /disorder proneness /risk; dysbarism; exercise; fluid flow; functional magnetic resonance imaging; human middle age (35-64); human subject; hypoxia; interstitial; lung imaging /visualization /scanning; mechanical stress; pathologic process; pulmonary circulation; pulmonary edema; respiratory airway pressure; vasoconstriction; young adult human (21-34)

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.

描述（由申请人提供）：该提案旨在了解肺血流分布的空间异质性和增加的肺毛细血管压力如何相互作用以影响肺水肿的发展。高原肺水肿（HAPE）是一种可能致命的急性水肿，被用作疾病模型，以便研究肺水肿的机制，而不会混淆败血症或多器官衰竭等变量。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在高压下尚未解决。该提议的总体假设是，HAPE 易感性增加需要缺氧引起的灌注不均匀性增加和肺血管压力增加，导致流量和压力增加的肺部区域水肿。使用称为动脉自旋标记 (ASL) 的定量功能磁共振成像 (fMRI) 技术，我们之前已经表明，HAPE 易感受试者在常压缺氧期间，单个等重力平面中的局部肺血流变得不太均匀，这一发现尚未观察到在 HAPE 抵抗受试者中，支持这一想法。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 在海平面的整个肺部进行测量，并使用非对比多用途测量仪测量与局部血管外液体增加相关的变化。回波 MR I 技术。这将有助于深入了解水肿的机制，因为如果不均匀的缺氧性肺血管收缩是毛细血管收缩前的现象，那么高毛细血管压力（和液体积聚）将出现在高流量（收缩较少）区域，暴露于高压力下。由于小动脉阻力低而导致肺动脉压力。相反，在低流量的肺部区域发现水肿可能意味着毛细血管后静脉收缩。将评估肺血管反应的解剖学再现性，以确定缺氧引起的灌注变化模式是否区域稳定，或者高流量区域是否随时间改变其解剖位置。如果它们在区域上可重复，则表明某些肺部区域存在固有的结构异常，而解剖学上可变的反应则表明主要是动态的相互依赖的过程。最后，将评估适应和运动（HAPE 的重要调节因素）对灌注不均匀性增加和由此产生的积液的影响。这些研究的结果可能有助于了解在压力条件下，当肺血管压力增加且可用氧气减少时，液体如何在肺部积聚。特别是，通过评估肺部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，并预测那些有肺水肿风险的人。