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疗问题。在这项拨款申请中，我们建议开发非侵入性肺形态测量作为这种衰弱性疾病的改进诊断。我们的技术是基于扩散MRI与超极化3 He气体，并允许在体内3D断层扫描估计肺泡表面积，肺泡密度，和腺泡气道半径-参数已被肺生理学家使用了几十年的金标准量化肺气肿，但以前只能通过侵入性肺活检测量。 作为上一个资助期的一部分，我们获得了30名已知有吸烟史的肺气肿早期受试者的体内肺形态测量数据。这些数据揭示了肺形态测量的非常具体的变化，这是常规临床试验所不理解的，表明我们的技术是检测肺微观结构早期变化的非常敏感的工具。本更新申请的主要目标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）扩展我们目前的肺部气体扩散的数学模型，将进行性肺组织破坏对3 He气体扩散的影响纳入其中;（ii）非侵入性地建立一系列年龄段的无吸烟史的健康人类受试者的肺部微观结构的基线参数;（iii）非侵入性地表征肺气肿的初始到晚期阶段的受试者的肺微观结构的变化;（iv）针对直接形态测量验证我们的技术。 总体而言，我们建议进一步开发和验证我们先进的MRI技术，用于人类肺部成像，作为肺气肿变化的上级特异性表征，并应用这些技术来提高我们对肺气肿中发生的微结构变化的理解，跨越广泛的年龄和疾病阶段。从肺泡变形的初始发作到晚期阶段，肺功能急剧丧失为特征，将阐明肺气肿进展时肺泡水平肺微观结构变化的全面情况。我们的新方法足够灵敏，可以早期检测和诊断肺气肿，提供改善患者治疗结果的机会，并有可能提供安全和非侵入性的体内生物标志物，用于在临床试验中监测药物疗效。 公共卫生相关性：本研究的主要目的是进一步发展我们先进的MRI技术，用于人体肺部成像-体内肺形态测量-作为肺气肿变化的上级、更灵敏的表征，并应用该技术来促进我们对肺气肿中发生的肺泡和气道变化的理解，跨越广泛的年龄和疾病阶段。该技术基于使用超极化3 He气体的扩散MRI。这些结果将为肺气肿的进展提供新的临床见解，从肺泡变形的最初开始到以肺功能急剧丧失为特征的最终阶段。

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.