Influence of spatial patterns of ventilation & perfusion on gas exchange in COPD

描述（由申请人提供）：本申请提出a .科特尼·亨德森博士的职业发展计划。作为与Kim Prisk博士（导师）合作的博士后，她使用MRI研究了肺水和重力对肺血流分布的影响。在博士后培训的剩余时间里，她将在Peter Wagner博士（共同导师）的指导下学习如何将多重惰性气体消除技术（MIGET）应用于慢性阻塞性肺疾病（COPD）患者。加州大学圣地亚哥分校的研究环境非常好，在John West博士和Peter Wagner博士的领导下，生理学部30多年来一直处于世界一流水平。本研究计划将研究COPD中以通气灌注比（VA/Q）不平等为特征的气体交换缺陷的生理机制。低氧肺血管收缩（HPV）减少慢性阻塞性肺病的VA/Q错配。总体假设是，不同的总体VA/Q不平等、通气和血流的空间模式以及HPV对COPD血流分布的影响反映了该疾病是以肺气肿（肺组织破坏）为主还是以气道疾病为主。使用MRI测量肺血流、通气和VA/Q的空间分布，使用MIGET测量总体VA/Q不平等。以肺气肿或气道疾病为主的慢性阻塞性肺病患者和年龄匹配的健康受试者将在呼吸空气和高氧气体以缓解HPV的同时进行研究。以下主要假设将被检验：(1)在肺气肿优势型患者中，高VA/Q区域的主要原因是肺组织和毛细血管破坏导致的低灌注，其空间分布是通气和血流异质性的重要决定因素；(2)在气道疾病优势型患者中，低VA/Q区域的主要原因是支气管阻塞导致的低通气；(3) HPV的空间格局是影响VA/Q总体不平等类型和血流空间异质性的重要机制。我们将与加州大学圣地亚哥分校临床研究中心PI的Joe Ramsdell医学博士合作，开展由NIH资助的COPD多中心遗传流行病学（COPDGene）项目，为大量具有良好特征的COPD患者提供机会。COPDGene研究的总体目标是确定COPD的遗传危险因素。COPDGene的目标与这一提议高度协同，从而允许基于生理机制表征COPD亚型。相关性（见说明）：慢性阻塞性肺病是全球第四大死因，到2020年将成为第三大死因。在美国国立卫生研究院资助的COPDGene研究中，结合使用MIGET和MRI对一组特征明确的COPD患者提出的假设进行验证，将有助于深入了解COPD亚型的潜在生理学，因此可能有助于当前药物治疗的最佳患者选择，并为未来的治疗提供途径。

DESCRIPTION (provided by applicant): This application proposes a career development plan for Dr. A. Cortney Henderson. As a postdoctoral fellow working with Dr. Kim Prisk (mentor), she studied the effects of lung water and gravity on the distribution of pulmonary blood flow using MRI. During the remainder of her postdoctoral training, she will learn how to apply the multiple inert gas elimination technique (MIGET) in chronic obstructive pulmonary disease (COPD) patients under Dr. Peter Wagner (co-mentor). The research environment at UCSD is excellent, and the Division of Physiology under the leadership of Dr. John West and Dr. Peter Wagner has been among the best in the world for over 30 years. The proposed research plan will study physiological mechanisms associated with the gas exchange defects in COPD, which is characterized by ventilation-perfusion ratio (VA/Q) inequality. Hypoxic pulmonary vasoconstriction (HPV) reduces VA/Q mismatch in COPD. The overall hypothesis is that differing overall VA/Q inequalities, spatial patterns of ventilation and blood flow, and effects of HPV on the distribution of blood flow in COPD reflect whether the disease is predominantly emphysema (lung tissue destruction) or predominantly airway disease. The spatial distribution of pulmonary blood flow, ventilation, and VA/Q will be measured using MRI and overall VA/Q inequality measured using MIGET. COPD patients presenting with predominantly emphysema or predominantly airway disease and age-matched healthy subjects will be studied while breathing air and then a hyperoxic gas to alleviate HPV. The following key hypotheses will be tested: (1) in emphysema predominant patients, the primary cause of regions of high VA/Q is low perfusion due to lung tissue and capillary destruction, the spatial distribution of which is an important determinant of the heterogeneity of ventilation and blood flow, (2) in airway disease predominant patients, the primary cause of regions of low VA/Q is low ventilation due to bronchial obstruction, and (3) the spatial pattern of HPV is an important mechanism contributing to the type of overall VA/Q inequality and spatial heterogeneity of blood flow. We will collaborate with Joe Ramsdell, M.D., UCSD Clinical Study Center PI for the multi-center Genetic Epidemiology of COPD (COPDGene) project funded by NIH, providing access to a large number of well-characterized COPD patients. The overall goal of the COPDGene study is to identify the genetic risk factors in COPD. The aims of COPDGene are highly synergistic with this proposal, thus allowing for characterization of the subtypes of COPD based on physiological mechanisms. RELEVANCE (See instructions): COPD is the 4th leading cause of death worldwide, and will be the 3rd leading cause of death by 2020. Combined use of MIGET and MRI to address the proposed hypotheses for a well-characterized group of COPD patients participating in the NIH-funded COPDGene study will provide insight into the underlying physiology in the subtypes of COPD, and therefore may facilitate optimal patient selection for current medical treatments as well as provide pathways for future therapies.