Time-Resolved 129Xe Ventilation-Perfusion MRI in Models of Acute Lung Injury

急性肺损伤模型中的时间分辨 129Xe 通气-灌注 MRI

• 批准号: 9336347
• 负责人: ZACKARY I CLEVELAND
• 金额: $ 23.64万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336347
• 关键词: Acute Lung Injury; Age; Alveolar; Animal Model; Animals; Atelectasis; Award; Blood; Blood Vessels; Breathing; Clinical; Clinical Research; Clinical Trials; Contrast Media; Coupled; Data; Data Analyses; Disease Progression; Environmental air flow; Etiology; Evolution; Experimental Designs; Fostering; Functional Imaging; Future; Gases; Goals; Health; Heterogeneity; Hour; Human; Hypoxemia; Hypoxia; Image; Impairment; Incidence; Infusion procedures; Injury; Irrigation; Laboratory Study; Lead; Lung; Lung diseases; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mentors; Methodology; Methods; Mission; Modeling; Molecular; Monitor; Mus; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Perfusion; Perfusion Weighted MRI; Phase; Physiological; Physiology; Pneumonia; Public Health; Pulmonary Ventilation; Rattus; Research; Research Support; Resolution; Respiratory Failure; Respiratory physiology; Risk Factors; Rodent; Rodent Model; Route; Saline; Sepsis; Shunt Device; Signal Transduction; Spatial Distribution; Techniques; Testing; Time; Training; Trauma; Tweens; United States; United States National Institutes of Health; Validation; Vasodilation; Water; Work; base; data acquisition; human disease; imaging modality; improved; innovation; insight; lung imaging; lung injury; mortality; pre-clinical; pre-clinical research; prevent; pulmonary function; temporal measurement; tool; vasoconstriction

Despite decades of research, incidence and mortality in Acute Lung Injury (ALI) remain high, and relationships between the cellular and molecular details of ALI and their physiological manifestations remain poorly under- stood. While these details can be elucidated using small animal models, the physiological consequences are difficult to quantify, because current measures of lung function in rodents provide inadequate temporal and spatial resolution. Moreover, this methodological gap represents a substantial barrier to preclinically assessing the efficacy of ALI treatments. The long-term goal of this research is to develop an imaging modality that can quantify all spatial and temporal aspects of pulmonary function in small animal models of ALI by using a single agent—hyperpolarized (HP) 129Xe—to rapidly image pulmonary ventilation (V) and perfusion (Q). The objective of this application is to use 3D 129Xe magnetic resonance imaging (MRI) to quantitatively map the V/Q ratio in rats and measure spatial and temporal changes in the V/Q distribution following injury. The central hypothesis underlying this proposal is that MR images obtained after inhaling 129Xe and during extracorporeal (EC) infu- sion of 129Xe into the blood will be able to rapidly visualize the 3D, V/Q distribution. This hypothesis is based on a detailed model of HP 129Xe signal dynamics and preliminary data demonstrating 3D, 129Xe MR images that reflect V and Q. The rationale for the proposed research is that V/Q mismatching is known from clinical trials to be exceedingly important in the pathological progression of ALI. Thus, V/Q matching must be assessed to fully characterize small animal models of injury and test potential treatments. Guided by strong preliminary data, our central hypothesis will be tested by the following three Specific Aims: 1) optimize the spatial and temporal reso- lution of HP 129Xe V/Q MRI and establish the baseline V/Q distribution in healthy rats; 2) test the ability of gas- phase 129Xe MRI to follow V/Q evolution after injury in airway and vascular occlusion models; and 3) develop dissolved 129Xe MRI during EC infusion and test the ability of this technique to detect perfusion in an ALI mod- el, when hypoxic vasoconstriction is impaired. Specifically, Aim 3 will test the hypothesis that dissolved 129Xe MRI can visualize impaired hypoxic vasoconstriction after nonselective vasodilation in a saline lavage model of ALI. Aim 1 will be conducted in the Mentored Phase (K99) of this Pathway to Independence Award, and Aim 3 will be conducted primarily in the Independent Phase (R00). The research proposed in Aim 2 will be split be- tween the K99 and R00 phases. The proposed research is innovative in that it will enable repeated, 3D map- ping of the V/Q distribution with isotropic (~1 mm) resolution in rat models of ALI within minutes, using a single agent. The proposed research is significant because it will enable previously inaccessible aspects of pathology that are known to be important in clinical ALI, namely the V/Q distribution, to be quantified in small animals. Ultimately, the methodological advances made possible by the proposed research will enable more complete validation of rodent models of ALI and establish a preclinical platform for evaluating ALI treatments.

尽管进行了数十年的研究，急性肺损伤 (ALI) 的发病率和死亡率仍然很高，而且两者之间的关系 ALI 的细胞和分子细节及其生理表现之间的关系仍然知之甚少。 虽然可以使用小动物模型来阐明这些细节，但其生理后果却是。 难以量化，因为目前对啮齿类动物肺功能的测量提供了不足的时间和 此外，这种方法上的差距对临床前评估构成了巨大障碍。 这项研究的长期目标是开发一种能够实现 ALI 治疗效果的成像方式。 通过使用单个 ALI 小动物模型来量化肺功能的所有空间和时间方面 超极化 (HP) 129Xe 试剂可快速对肺通气 (V) 和灌注 (Q) 进行成像。 该应用的主要目的是使用 3D 129Xe 磁共振成像 (MRI) 来定量绘制 V/Q 比 大鼠并测量受伤后 V/Q 分布的空间和时间变化。 该提议的基础是吸入 129Xe 后和体外 (EC) 输注期间获得的 MR 图像 将 129Xe 注入血液中将能够快速可视化 3D V/Q 分布。 HP 129Xe 信号动态的详细模型和初步数据展示了 3D、129Xe MR 图像， 反映 V 和 Q。拟议研究的基本原理是，从临床试验中已知 V/Q 不匹配 因此，必须对 V/Q 匹配进行全面评估。 在强有力的初步数据的指导下，我们描述了小动物损伤模型并测试了潜在的治疗方法。 中心假设将通过以下三个具体目标进行检验：1）优化空间和时间分辨率 HP 129Xe V/Q MRI 的稀释并建立健康大鼠的基线 V/Q 分布 2) 测试气体的能力； 129Xe MRI 跟踪气道和血管闭塞模型损伤后的 V/Q 演变；3) 开发 在 EC 输注过程中溶解 129Xe MRI，并测试该技术检测 ALI 模型中灌注的能力 具体而言，当缺氧血管收缩受损时，目标 3 将检验溶解 129Xe 的假设。 MRI 可以显示在盐水灌洗模型中非选择性血管舒张后受损的缺氧血管收缩。 ALI。目标 1 将在独立之路奖的指导阶段 (K99) 中进行，目标 3 将在该独立之路奖的指导阶段进行。 将主要在独立阶段（R00）进行 目标 2 中提出的研究将分为： 所提出的研究是创新的，因为它将实现重复的 3D 地图。 在几分钟内，使用单个 拟议的研究意义重大，因为它将实现以前无法触及的病理学方面。 已知在临床 ALI 中很重要，即 V/Q 分布，可在小动物中进行量化。 最终，拟议研究所带来的方法论进步将使更完整的研究成为可能。 验证 ALI 啮齿动物模型并建立评估 ALI 治疗的临床前平台。