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

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，而且与 ALI的细胞和分子细节与其生理表现之间的关系尚不清楚。 站着。虽然这些细节可以通过小动物模型来阐明，但其生理后果是 很难量化，因为目前对啮齿动物肺功能的测量提供了不充分的时间和 空间分辨率。此外，这一方法学上的差距是临床前评估的重要障碍。 ALI治疗的疗效。这项研究的长期目标是开发一种能够 在ALI的小动物模型中，使用单一的 试剂-超极化(HP)129Xe-快速成像肺通气量(V)和血流灌注量(Q)。目标是 这一应用的目的是使用3D 129Xe磁共振成像(MRI)来定量绘制V/Q比 并测量损伤后V/Q分布的空间和时间变化。中心假说 这一建议的基础是，吸入129Xe后和体外循环(EC)期间获得的磁共振图像- 将129Xe离子注入血液将能够快速可视化3D、V/Q分布。这一假设是基于 HP 129Xe信号动力学的详细模型和演示3D、129Xe磁共振图像的初步数据 反映V和Q。拟议研究的基本原理是V/Q不匹配从临床试验到 在ALI的病理进程中起着极其重要的作用。因此，必须对V/Q匹配进行全面评估 描述损伤的小动物模型，并测试可能的治疗方法。在强劲的初步数据指引下，我们的 中心假设将通过以下三个具体目标进行检验：1)优化空间和时间分辨率。 Hp-129Xe V/Q磁共振成像，建立正常大鼠的基础V/Q分布； 129Xe期MRI追踪气道和血管闭塞模型损伤后的V/Q变化；3)发展 在EC输注过程中溶解129Xe磁共振，并测试该技术在ALI模型中检测血流灌注的能力。 EL，当缺氧性血管收缩受损时。具体地说，Aim 3将测试溶解129Xe的假设 MRI可以显示非选择性血管扩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指导阶段(K99)进行，目标3 将主要在独立阶段(R00)进行。目标2建议的研究将分为以下几个部分： 在K99和R00阶段之间。这项拟议的研究具有创新性，因为它将使重复的3D地图- 在几分钟内以各向同性(~1 mm)分辨率对大鼠ALI模型的V/Q分布进行ping，使用单一的 探员。这项拟议的研究意义重大，因为它将使以前无法理解的病理学方面成为可能。 这在临床ALI中是重要的，即V/Q分布，将在小动物中进行量化。 最终，拟议的研究使方法学上的进步成为可能，将使 验证ALI的啮齿动物模型，建立评价ALI治疗的临床前平台。

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.