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，并且ALI的细胞和分子细节之间的关系及其生理表现仍然很差。虽然可以使用小动物模型阐明这些细节，但生理后果很难量化，因为啮齿动物中肺功能的当前度量提供了时间和空间分辨率不足。此外，该方法论差距代表了临床上评估ALI处理功效的重大障碍。这项研究的长期目标是开发一种成像方式，可以通过使用单个药物 - 磨砂（HP）129xE到快速图像肺通风（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。该应用的目的是使用3D 129XE磁共振成像（MRI）定量绘制大鼠的V/Q比，并测量受伤后V/Q分布的空间和时间变化。该提议的基础假设是吸入129 xe和体外（EC）（EC）将129 XE输注到血液中获得的MR图像将能够迅速可视化3D，V/Q分布。该假设基于HP 129XE信号动力学的详细模型和初步数据，证明了反映V和Q的3D，129XE MR图像。拟议的研究的基本原理是，从临床试验中知道V/Q不匹配在ALI的病理进展中非常重要。因此，必须评估V/Q匹配，以充分表征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，我们的中心假设将通过以下三个特定目的来检验：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）测试气道和血管闭塞模型受伤后v/q演化的气体129xE MR的能力； 3）在输注过程中，在缺氧血管收缩受损时，会在EC输注过程中开发溶解的129XE MRI，并测试该技术在Ali Mod- El中检测灌注的能力。具体而言，AIM 3将检验以下假设：溶解的129XE MRI可以在ALI盐水灌洗模型中非选择性血管舒张后可视化受损的低氧血管收缩。 AIM 1将在该奖励途径的指导阶段（K99）进行，AIM 3将主要在独立阶段（R00）进行。 AIM 2中提出的研究将在K99和R00阶段之间进行分配。拟议的研究具有创新性，因为它将使用单个药物在几分钟内使用各向同性（〜1 mm）分辨率的V/Q分布进行重复的3D映射。拟议的研究很重要，因为它将使以前无法访问的病理学方面在临床ALI中很重要，即V/Q分布在小动物中进行量化。最终，拟议的研究使方法学进步成为可能，将使ALI的啮齿动物模型更完整地验证，并建立一个评估ALI治疗的临床前平台。