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

 描述(申请人提供)：慢性阻塞性肺疾病(COPD)已成为美国第三大常见死亡原因，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的发展和进展。虽然对COPD的研究已经从不同的角度评估了肺的生理、病理和功能，但关于腺泡通道的结构和作用的活体信息很少，尽管这些通道占肺体积的95%，是主要的气体交换单位。这项建议的首要目标是通过测量和区分这些条件下腺泡呼吸道结构变化的所有方面，对衰老、吸烟和COPD对肺的影响有一个新的理解。我们还旨在了解小导气管疾病和气体捕捉区腺泡气道结构变化之间的相互作用，这被认为是导致肺气肿的早期事件。在我们先前发现的腺泡内各向异性3He气体扩散的基础上，我们开发并验证了利用超极化3He磁共振成像(MRI)进行肺形态测量的创新成像技术，为本研究提供了关于腺泡内气道结构和空间分布的独特的在体定量信息。我们将结合3He形态测量数据和定量CT数据，获得有关实质(包括毛细血管)和非实质(非毛细血管等)的独特信息。肺组织，以及小传导呼吸道的疾病。我们的具体目标集中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：通过使用基于MRI的活体肺形态测量和定量CT确定的定量指标，识别和比较“健康”不吸烟者和“健康”吸烟者随年龄增长而导致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。目的：探讨吸烟相关性COPD患者肺功能进行性恶化的结构机制，并利用基于MRI的活体肺形态计量学和定量CT定量测量方法，区分非吸烟者和吸烟者的腺泡和小气道与COPD患者年龄相关性结构改变的机制。我们期望开发一种新的方法来评估衰老和COPD对肺结构和功能的影响，对衰老、吸烟和肺气肿如何引起肺腺泡结构改变和相关的肺功能恶化提供新的理解，并为预防和治疗COPD这一主要公共卫生问题提供新的靶点。

 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.