In vivo human lung morphometry with hyperpolarized 3He MRI and CT: effects of aging, smoking, and COPD

 描述（由申请人提供）：慢性阻塞性肺病（COPD）已成为美国第三大常见死因，与COPD相关的死亡人数在过去20年中翻了一番。年龄、环境和遗传因素影响COPD的发生和进展。虽然COPD的研究已经评估了肺生理学、病理学和功能的不同方面，但是关于腺泡气道的结构和作用的体内信息非常少，即使这些气道占肺体积的95%并且作为主要的气体交换单元起作用。该提案的总体目标是通过测量和区分这些条件中腺泡气道结构变化的所有方面，对衰老、吸烟和COPD对肺的影响进行新的理解。我们的目的也是了解疾病之间的相互作用，小传导气道和变化的腺泡气道的结构中的气体捕获的区域，这被认为是早期事件导致肺气肿。 基于我们先前发现的腺泡气道中各向异性3He气体扩散，我们开发并验证了超极化3He磁共振成像（MRI）肺形态测量的创新成像技术，该技术为本研究提供了腺泡气道结构和空间分布的独特体内定量信息。我们将联合收割机3He形态测量数据与定量CT数据相结合，以获得关于实质（肺泡壁，包括毛细血管）和非实质（非毛细血管等）的独特信息。肺组织，以及小传导气道的疾病。我们的具体目标专注于建立腺泡和小气道结构改变与肺功能下降之间的定量关系：目标1：识别和比较“健康”从不吸烟者和“健康”吸烟者中与衰老相关的肺功能进行性恶化的结构机制，并区分腺泡和小气道疾病的贡献，通过使用由基于MRI的体内肺形态测定法和定量CT确定的定量度量。 目标二：通过使用基于MRI的体内肺形态测量和定量CT确定的定量指标，确定与吸烟相关的COPD相关的肺功能进行性恶化的结构机制，并区分腺泡和小气道（“健康”从不吸烟者和“健康”吸烟者）中年龄相关结构变化的机制与COPD所致的机制。 我们希望开发一种新的方法来评估老化和COPD对肺结构和功能的影响，提供一个新的认识，如何老化，吸烟和肺气肿导致肺腺泡结构的变化和相关的肺功能恶化，并提出新的目标，预防和治疗COPD的主要公共卫生问题。

 DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) has become the third most common cause of death in the U.S., and the number of COPD-associated deaths has doubled over the past 20 years. Age, environmental, and genetic factors affect COPD development and progression. While studies of COPD have evaluated different aspects of lung physiology, pathology, and function very little in vivo information exists on the structure and the role of the acinar airways, even though these airways represent 95% of the lung volume and function as the major gas-exchanging unit. This proposal has an overarching goal of developing a new understanding of the effects of aging, cigarette smoking, and COPD on the lung, by measuring and differentiating all aspects of the structural changes in acinar airways among these conditions. We also aim to understand the interplay between disease of small conducting airways and changes in the structure of acinar airways in regions of gas trapping which are thought to be early events leading to emphysema. Building on our prior discovery of anisotropic 3He gas diffusion in acinar airways, we developed and validated the innovative imaging technique of lung morphometry with hyperpolarized 3He magnetic resonance imaging (MRI) that provides unique in vivo quantitative information on the structure and spatial distribution of acinar airways for this study. We will combine 3He morphometric data with quantitative CT data to obtain unique information on parenchymal (alveolar walls including capillaries) and non-parenchymal (non-capillary vessels, etc.) lung tissue, as well as on disease of small conducting airways. Our Specific Aims focus on establishing quantitative relationships between structural alterations in acinar and small airways and declines in lung function: Aim 1: Identify and compare structural mechanisms of the progressive deterioration in lung function associated with aging in "healthy" never-smokers and "healthy" smokers, and differentiate contributions of acinar and small airway disease, by using quantitative metrics determined by MRI-based in vivo lung morphometry and quantitative CT. Aim 2: Identify the structural mechanisms of the progressive deterioration in lung function associated with smoking-related COPD, and differentiate the mechanisms of age-related structural changes in the acinar and small airways (in "healthy" never-smokers and "healthy" smokers) from those due to COPD, by using quantitative metrics determined by MRI-based in vivo lung morphometry and quantitative CT. We expect to develop a new approach for assessing the effects of aging and COPD on lung structure and function, provide a new understanding of how aging, cigarette smoking, and emphysema cause lung acinar structural changes and associated deterioration in lung function, and propose novel targets for preventing and treating the major public health problem of COPD.