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.

尽管经过几十年的研究，急性肺损伤（ALI）的发病率和死亡率仍然很高， 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， 站着。虽然这些细节可以用小动物模型来阐明，但生理后果是 难以量化，因为目前啮齿动物肺功能的测量提供的时间和 空间分辨率此外，这种方法上的差距是临床前评估的一个重大障碍， ALI治疗的有效性。这项研究的长期目标是开发一种成像方式， 通过使用单一的定量方法，在ALI的小动物模型中量化肺功能的所有空间和时间方面， 超极化（HP）129 Xe-快速成像肺通气（V）和灌注（Q）。客观 本申请的一个目的是使用3D 129 μ m磁共振成像（MRI）来定量地绘制 并测量损伤后V/Q分布的空间和时间变化。核心假设 这一建议的基础是，吸入129微克后和体外（EC）输注期间获得的MR图像， 将129 μ m的放射性粒子注入血液将能够快速地显现3D、V/Q分布。这个假设是基于 HP 129 MRI信号动力学的详细模型和初步数据，显示3D、129 MRI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， 在急性肺损伤的病理进展中非常重要。因此，必须评估V/Q匹配， 表征小动物损伤模型并测试潜在治疗。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）优化空间和时间资源， 方法：（1）测定健康大鼠的HP 129 mV/Q MRI的V/Q分布，建立正常大鼠的V/Q分布基线; 在气道和血管闭塞模型中追踪损伤后的V/Q演变的129相MRI;以及3）开发 在EC输注过程中溶解129 μ M MRI，并测试该技术检测ALI模型中灌注的能力， 当缺氧性血管收缩受损时。具体来说，目标3将测试溶解129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性血管收缩。 阿里目标1将在本独立之路奖的辅导阶段（K99）进行，目标3将在本独立之路奖的辅导阶段（K99）进行。 将主要在独立阶段（R 00）进行。目标2中提出的研究将分为- 在K99和R 00相之间。拟议的研究是创新的，因为它将使重复的，3D地图- 在ALI大鼠模型中，使用单次超声心动图，在数分钟内以各向同性（~1 mm）分辨率对V/Q分布进行了定位。 剂这项拟议中的研究意义重大，因为它将使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，在小动物中进行定量。 最终，拟议研究所带来的方法学进步将使更全面的研究成为可能。 确认ALI的啮齿动物模型，并建立评估ALI治疗的临床前平台。