QUANTIFICATION OF LUNG VENTILATION AND STRUCTURE BY 3HE MRI

描述（由申请人提供）：肺气肿是美国和世界范围内的主要医学问题。在这项拨款申请中，我们建议发展无创肺形态测定法，作为这种使人衰弱的疾病的改进诊断。我们的技术是基于超极化3He气体的弥散MRI，并允许体内三维断层扫描估计肺泡表面积，肺泡密度和腺泡气道半径-这些参数已被肺生理学家用作量化肺气肿的金标准几十年，但以前只能通过侵入性肺活检来测量。作为先前资助期的一部分，我们获得了30名已知有早期肺气肿吸烟史的受试者的体内肺形态测量数据。这一数据揭示了肺形态测量学的非常特殊的变化，这是传统临床试验无法发现的，这表明我们的技术是一种非常敏感的检测肺微观结构早期变化的工具。本更新申请的主要目的是将体内肺形态测定技术用于识别肺实质结构变化的诊断潜力扩展到肺气肿的所有阶段。为了实现这一目标，我们将：(i)通过纳入渐进式肺组织破坏对3He气体扩散的影响，扩展我们目前肺部气体扩散的数学模型；（ii）非侵入性地建立一系列年龄类别中无吸烟史的健康人的肺微观结构基线参数；（iii）非侵入性表征肺气肿初期至晚期受试者肺部微观结构的变化；（iv）通过直接形态测量验证我们的技术。总之，我们建议进一步发展和验证我们先进的人类肺部成像MRI技术，作为肺部肺气肿变化的优越、特异性表征，并应用这些技术来提高我们对肺气肿发生的微观结构变化的理解，跨越广泛的年龄和疾病阶段。肺气肿发展过程中肺泡水平肺微观结构变化的全面图景将被阐明，从肺泡变形的初始发作到以肺功能显著丧失为特征的晚期阶段。我们的新方法具有足够的灵敏度，可以早期发现和诊断肺气肿，为改善患者的治疗结果提供机会，并有可能为临床试验中监测药物疗效提供安全、无创的体内生物标志物。

DESCRIPTION (provided by applicant): Emphysema is a major medical problem in the US and worldwide. In this grant application we propose to develop non-invasive lung morphometry as an improved diagnostic of this debilitating disease. Our technique is based on diffusion MRI with hyperpolarized 3He gas and allows in vivo 3D tomographic estimation of the lung alveolar surface area, alveolar density, and acinar airway radii - parameters that have been used by lung physiologists for decades as the gold standard for quantifying emphysema but were previously only measurable through invasive lung biopsy. As part of the previous grant period, we obtained in vivo lung morphometry data on 30 subjects with known smoking histories in the early stages of emphysema. This data revealed very specific changes in lung morphometry which were not appreciated with conventional clinical tests, suggesting that our technique is a very sensitive tool for detecting early changes in the lung microstructure. The main goal of this Renewal Application is to extend the diagnostic potential of the in vivo lung morphometry technique for identifying structural changes in lung parenchyma to all stages of emphysema. To achieve this goal we will: (i) extend our current mathematical model of gas diffusion in lungs by incorporating the effects of progressive lung tissue destruction on 3He gas diffusion; (ii) non-invasively establish the baseline parameters of lung microstructure in healthy human subjects without smoking histories over a range of age categories; (iii) non-invasively characterize the changes in lung microstructure for subjects in the initial through advanced stages of emphysema; (iv) validate our technique against direct morphometric measurements. Overall, we propose to further develop and validate our advanced MRI techniques for imaging of the human lung as superior, specific characterization of emphysematous changes in lung, and apply these techniques to advance our understanding of the microstructural changes that occur in emphysema, across a wide range of age and disease stages. A comprehensive picture of the changes in lung microstructure at the alveolar level with emphysema progression will be elucidated, from the initial onset of alveolar deformation to the advanced stages, characterized by a dramatic loss of lung function. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and non-invasive in vivo biomarkers for monitoring drug efficacy in clinical trials. PUBLIC HEALTH RELEVANCE: The main goal of this study is to further develop our advanced MRI technique for imaging of the human lung - in vivo lung morphometry - as a superior, more sensitive characterization of emphysematous changes, and apply this technique to advance our understanding of the changes in lung alveoli and airways that occur in emphysema, across a wide range of ages and disease stages. This technique is based on diffusion MRI with hyperpolarized 3He gas. The results will provide new clinical insights into emphysema progression, from the initial onset of the alveolar deformation to the final stages, characterized by dramatic loss of lung function.