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，但急性肺损伤（ALI）的死亡和死亡率仍然很高，并且关系 在Ali的细胞和分子细节之间，其身体表现仍然很差 站了起来。尽管可以使用小动物模型阐明这些细节，但物理后果是 很难量化，因为啮齿动物中肺功能的当前措施提供了暂时不足的 空间分辨率。此外，该方法论差距代表了临床上评估的实质性障碍 阿里治疗的效率。这项研究的长期目标是开发一种成像方式，可以 通过使用一个单一 试剂 - 偏振（HP）129XE-快速图像肺通风（V）和灌注（Q）。目标 此应用的是使用3D 129XE磁共振成像（MRI）定量映射V/Q比率 大鼠并测量受伤后V/Q分布的空间和临时变化。中心假设 该提案的基础是吸入129 XE和体外（EC）期间获得的MR图像 在血液中的129倍将能够迅速形象化3D，v/q分布。该假设基于 HP 129XE信号动力学和初步数据的详细模型，证明了3D，129XE MR图像 反映V和Q。拟议的研究的基本原理是，从临床试验到 在ALI的病理发展中至关重要。那就是v/q匹配必须完全评估 表征了损伤和测试潜在治疗的小动物模型。在强大的初步数据的指导下，我们 中央假设将通过以下三个特定目的进行检验：1）优化空间和临时回旋 HP 129XE V/Q MRI的流并建立了健康大鼠中的基线V/Q分布； 2）测试气体的能力 - 在气道和血管遮挡模型中受伤后的v/q演化阶段的129XE阶段MRI； 3）发展 EC输注期间溶解了129XE MRI，并测试了该技术在ALI模型中检测灌注的能力 EL，当缺氧血管收缩受损时。具体而言，AIM 3将检验溶解129XE的假设 MRI可以在非选择性血管舒张后可视化受损的低氧血管收缩。 阿里。 AIM 1将在该通往独立奖的指导阶段（K99）进行，并瞄准3 将主要在独立阶段（R00）进行。 AIM 2中提出的研究将被分割 鸣叫K99和R00阶段。拟议的研究具有创新性，因为它将使重复，3D地图 - 使用单一的p/q分布在ALI大鼠模型中用各向同性（〜1 mm）分辨率在几分钟内使用单一分辨率 代理人。拟议的研究很重要，因为它将启用以前无法访问的病理方面 已知在临床ALI中很重要，即V/Q分布，可以在小动物中进行量化。 最终，拟议的研究实现的方法论进步将使更完整 验证ALI的啮齿动物模型，并建立一个评估ALI处理的临床前平台。