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和肺毛细管压力增加的空间异质性如何相互作用，以影响肺水肿的发展。高空肺水肿（HAPE）是一种急性致命水肿，用作疾病模型，以允许研究肺水肿的机制，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，但是如何将肺毛细血管暴露于高压。该提案的总体假设是，增加对HAPE的易感性既需要缺氧引起的灌注异质性增加和肺血管压力增加，从而导致流量增加和压力增加的肺部水肿。使用定量功能磁共振成像（FMRI）技术称为动脉自旋标记（ASL），我们先前已经表明，在HAPE易感受试者中，在单一同种型缺氧中，区域肺血流在单个同育平面中变得均匀均匀在抗Hape的主题中，支持这个想法。缺氧和运动对肺血流空间分布的影响将在整个海平面，使用最先进的fMRI-ASL的状态在整个肺部，以及与非对比度多的局部血管外液相关的变化回声I Technique。这将允许对水肿的机制有所了解，因为如果不均匀的低氧肺血管收缩是毛细血管前的收缩，则高毛细血管压力（和液体积累）将发生在高流量（较少收缩）的区域，暴露于高的地区肺动脉压力由于低动脉抗性而引起的。在低流量的肺部地区发现水肿将暗示毛细血管后静脉内收缩。将评估肺血管反应的解剖学可重复性，以确定缺氧的灌注变化是否在区域稳定，或者高流动区域是否会随着时间的推移改变其解剖位置。如果它们在区域上可再现，这将表明某些肺部区域存在固有的结构异常，而解剖上可变的响应将表明主要动态相互依存的过程。最后，将评估适应性和锻炼（HAPE的重要调节因素）对灌注异质性增加和结果液积累的影响。这些研究的结果可能会提供有关当肺血管中的压力增加并减少可用氧气时的压力条件下肺中流体积聚的洞察力。特别是，通过评估肺中的血流与液体形成之间的关系，这项工作可以识别在某些条件下识别肺损伤的阈值，并预测有肺水肿风险的人。