Imaging regional physiologic parameters of lung function

描述(申请人提供)：该项目的长期目标是开发超极化MRI方法，用于预测和表征慢性阻塞性肺疾病(COPD)，这是一种普遍存在的肺部疾病，预计到2020年将成为美国第三大死亡原因。最近的出版物，包括我们的，都表明超极化气体磁共振技术对COPD在人类受试者和动物模型中的早期发病具有独特的敏感性。我们的方法是开发非侵入性超极化MRI技术，以在早期阶段发现这种疾病，并寻找新的治疗药物。在第一个资助周期中，我们设计和实施了各种方法来准确测量局部肺泡氧分压、通气量、灌注量和通气量/灌注率，以及氦-3在肺内的耗氧率和扩散率。我们已经评估了这些区域参数在肺功能和结构的定量评估中的应用。最令人兴奋的结果是：1)在组织学发现之前，肺气肿肺的区域通气性发生了显著变化；2)有灌注缺陷的肺的区域氧分压和区域通风/灌流比发生了显著变化；3)肺气肿肺的区域表观扩散系数值升高，与组织学密切相关；4)设计和制造了最先进的可编程呼吸机，能够向小动物和大型动物精确地输送氧、氮和超极化的氦-3的混合物；5)开发了用于定量测量区域灌注量的超极化碳13技术。这些方法是在动物模型中开发的，现在已经在几个地点转化为临床使用，以全面评估肺功能和结构。然而，到目前为止，这些非侵入性的方法还没有被用来描述肺气肿的潜在机制。目前的建议的目标是使用这些非侵入性的超极化氦-3MRI参数来研究导致肺气肿发展的潜在机制。具体地说，我们将1)通过长期暴露在香烟烟雾中诱导大鼠肺气肿模型；2)用超极化氦-3MRI标记物、已建立的CT参数、肺功能测试和组织学追踪肺气肿变化的进展；3)测量细胞凋亡分子标记的区域浓度，并通过超极化氦-3标记物识别疾病的发生；以及4)通过干扰特定的细胞凋亡途径，进一步了解疾病的发病机制并评估可能的干预措施。我们将使用许多先进和新颖的方法，包括超极化的氦-3MRI参数来定量评估肺功能，以及免疫组织学染色方法来测量肺组织中与细胞凋亡有关的分子特征，以实现这些目标。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop hyperpolarized MRI methods for the prediction and characterization of chronic obstructive pulmonary disease (COPD), a prevalent pulmonary disorder that is projected to become the third leading cause of death in the U.S. by 2020. Recent publications, including our, suggest that hyperpolarized gas MRI techniques are uniquely sensitive to the early onset of COPD in both human subjects and animal models. Our approach has been to develop noninvasive hyperpolarized MRI techniques to detect this disease in its early stages and to identify new therapeutic agents. During the first funding cycle we designed and implemented various methods to accurately measure regional alveolar partial pressure of oxygen, ventilation, perfusion, and ventilation-to-perfusion ratio, as well as oxygen depletion rate and diffusivity of helium-3 in the lung. We have evaluated the utility of these regional parameters in the quantitative assessment of lung function and structure. The most exciting results are: 1) significant changes in regional ventilation in emphysematous lungs that precede histological findings; 2) significant changes in the regional partial pressure of oxygen and regional ventilation-to-perfusion ratio in lungs with perfusion defects; 3) an elevated value of regional apparent diffusion coefficient of helium-3 in emphysematous lungs that correlates well with histology; 4) design and fabrication of a state-of-the-art programmable ventilator capable of delivering an accurate mixture of oxygen, nitrogen, and hyperpolarized helium-3 to both small and large animals; 5) development of hyperpolarized carbon-13 technology for the quantitative measurement of regional perfusion. These methods were developed in animal models and have now been translated to clinical use at several sites to comprehensively assess lung function and structure. However, these non-invasive methods have not, as yet, been used to characterize the underlying mechanisms of emphysema. The objectives of the current proposal are to use these non-invasive hyperpolarized helium-3 MRI parameters for studying the underlying mechanisms that lead to the development of emphysema. Specifically, we will 1) induce emphysema in a rat model using chronic exposure to cigarette smoke; 2) trace the progression of emphysematous changes with hyperpolarized helium-3 MRI markers, established CT parameters, pulmonary function tests, and histology; 3) measure the regional concentration of the molecular signatures of apoptosis and identify the onset of the disease through hyperpolarized helium-3 markers; and 4) further the understanding of disease pathogenesis and evaluate possible interventions in emphysema progression by disrupting specific apoptosis pathways We will employ a number of sophisticated and novel methods, including hyperpolarized helium-3 MRI parameters to quantitatively assess lung function and immunohistological staining methods to measure molecular signatures responsible for apoptosis in lung tissue, to achieve these goals.