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: 8514713
• 负责人: ZACKARY I CLEVELAND
• 金额: $ 8.41万
• 依托单位: DUKE UNIVERSITY
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514713
• 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; Disease Progression; Environmental air flow; Etiology; Evolution; 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; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mentors; Methods; Mission; Modality; Modeling; Molecular; Monitor; Mus; Outcome; 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; Staging; Techniques; Testing; Time; Training; Trauma; United States; Validation; Vasodilation; Water; Work; base; data acquisition; design; human disease; imaging modality; improved; innovation; insight; lung basal segment; lung injury; mortality; pre-clinical; pre-clinical research; prevent; pulmonary function; tool; vasoconstriction

DESCRIPTION (provided by applicant): 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) infusion 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 resolution of HP 129Xe V/Q MRI and establish the baseline V/Q distribution in healthy rats; 2) test the ability of gas- phase 129Xe MR 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 between the K99 and R00 phases. The proposed research is innovative in that it will enable repeated, 3D mapping 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.

描述（由申请人提供）：尽管经过数十年的研究，急性肺损伤（ALI）的发病率和死亡率仍然很高，并且 ALI 的细胞和分子细节与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阐明这些细节，但其生理后果难以量化，因为目前对啮齿类动物肺功能的测量提供的时间和空间分辨率不足。此外，这种方法上的差距对临床前评估 ALI 治疗的疗效构成了巨大障碍。本研究的长期目标是开发一种成像方式，通过使用单剂超极化 (HP) 129Xe 快速成像肺通气 (V) 和灌注 (Q)，可以量化 ALI 小动物模型中肺功能的所有空间和时间方面。此应用的目的是使用 3D 129Xe 磁共振成像 (MRI) 定量绘制大鼠的 V/Q 比值，并测量受伤后 V/Q 分布的空间和时间变化。该提议的核心假设是，吸入 129Xe 后以及将 129Xe 体外 (EC) 输注到血液中时获得的 MR 图像将能够快速可视化 3D、V/Q 分布。该假设基于 HP 129Xe 信号动力学的详细模型和展示反映 V 和 Q 的 3D、129Xe MR 图像的初步数据。拟议研究的基本原理是，从临床试验中已知 V/Q 不匹配在 ALI 的病理进展中极其重要。因此，必须评估 V/Q 匹配，以充分表征小动物损伤模型的特征并测试潜在的治疗方法。在强有力的初步数据的指导下，我们的中心假设将通过以下三个具体目标进行检验：1）优化 HP 129Xe V/Q MRI 的空间和时间分辨率，并在健康大鼠中建立基线 V/Q 分布； 2) 测试气相 129Xe MR 在气道和血管闭塞模型中跟踪损伤后 V/Q 演变的能力； 3）在 EC 输注过程中进行溶解 129Xe MRI，并测试该技术在缺氧血管收缩受损时检测 ALI 模型中灌注的能力。具体来说，目标 3 将测试以下假设：溶解 129Xe MRI 可以在 ALI 盐水灌洗模型中非选择性血管舒张后显示受损的缺氧血管收缩。目标 1 将在独立之路奖的指导阶段 (K99) 中进行，目标 3 将主要在独立阶段 (R00) 中进行。目标 2 中提出的研究将分为 K99 和 R00 阶段。拟议的研究具有创新性，因为它将能够使用单一试剂在几分钟内以各向同性（约 1 毫米）分辨率重复 3D 映射 ALI 大鼠模型中的 V/Q 分布。拟议的研究意义重大，因为它将能够在小动物中量化以前无法获得的已知在临床 ALI 中重要的病理学方面，即 V/Q 分布。最终，拟议研究所取得的方法学进展将使 ALI 啮齿动物模型得到更完整的验证，并建立一个评估 ALI 治疗的临床前平台。