Pulmonary Microvascular Blood Flow and Cor Pulmonale Parvus in Emphysema/COPD

肺气肿/慢性阻塞性肺病中的肺微血管血流和肺小病

• 批准号: 8632186
• 负责人: R Graham BARR
• 金额: $ 85.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-28 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632186
• 关键词: 3-Dimensional; Affect; Alveolar; Apoptosis; Atherosclerosis; Biological Markers; Blood Vessels; Blood flow; Cardiac Output; Cardiopulmonary; Cardiovascular system; Cause of Death; Chronic Obstructive Airway Disease; Clinical Trials; Complication; Data; Development; Environmental air flow; Etiology; Functional disorder; Future; Gene Expression; General Population; Genomics; Helium; Human; Hypoxemia; Hypoxia; Image; Impairment; Intervention; Link; Lung; Magnetic Resonance Imaging; Measures; Medical; Minority; Oxygen; Oxygen measurement, partial pressure, arterial; Partial Pressure; Participant; Pathogenesis; Patients; Perfusion; Peripheral Blood Mononuclear Cell; Phase; Physiological; Prevalence; Pulmonary Emphysema; Pulmonary Heart Disease; Pulmonary Ventilation; Randomized; Recruitment Activity; Residual state; Right Ventricular Function; Severities; Smoking; Stem cells; Structure of parenchyma of lung; Testing; Tissues; United States; Venous; Ventricular; Ventricular End-Diastolic Volumes; Work; X-Ray Computed Tomography; cellular imaging; clinically relevant; imaging modality; improved; innovation; longitudinal design; mortality; multimodality; novel; pressure; public health relevance; repaired; small airways disease; stem cell therapy; tiotropium bromide; vasoconstriction

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and in the United States. More than half of COPD patients have emphysema on computed tomography, which is associated with increased mortality, but medical therapies for COPD exclusively target the airways. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited 327 participants to test the endothelial hypothesis of emphysema, which posits that smoking-related pulmonary endothelial damage contributes to emphysema. The MESA COPD Study confirmed its primary aims that: pulmonary microvascular blood flow (PMBF) on magnetic resonance imaging (MRI) is substantially reduced COPD and emphysema of all severities; endothelial microparticles are increased and endothelial progenitor cells are reduced; and gene expression in peripheral blood mononuclear cells is strongly linked to PMBF. Although supportive of the endothelial hypothesis, findings also may be due to newly described aberrant hypoxic pulmonary vasoconstriction (HPV) or residual HPV from impaired ventilation. We also found that right ventricular (RV) volumes were reduced in COPD and emphysema, a condition we have termed cor pulmonale parvus. This condition is associated with all-cause mortality in the general population and might result, pilot data suggest, from RV stiffness and subtle ventilatory impairment. The renewal is a longitudinal continuation of the MESA COPD Study in which we aim to use regional measures of oxygen tension, ventilation, PMBF and emphysema, along with interventions to reverse HPV and to treat hyperinflation, and innovative measures of RV function and venous blood flow on MRI to test the hypotheses that: emphysema is characterized by reduced PMBF independent of HPV and ventilatory impairment; cor pulmonale parvus is associated with RV stiffness and increased intrathoracic pressure; and reduced PMBF in non-emphysematous regions of the lung is associated with the local development of emphysema and tissue loss at five years. Innovative aspects of this proposal include the use of novel MRI imaging modalities of direct clinical relevance, examination of a new entity, cor pulmonale parvus, and the longitudinal testing of the vascular hypothesis of emphysema in humans. Confirmation of these aims would create a paradigm shift in COPD treatment to justify the testing of existing and novel (e.g., EPC/stem cell) therapies targeted to the pulmonary vasculature in emphysema, provide a potential imaging biomarker to facilitate early phase, short-term clinical trials of such therapies, and suggest mechanisms to approach and possibly treat cor pulmonale parvus.

描述（由申请人提供）：慢性阻塞性肺病 (COPD) 是全球和美国的第三大死因。超过一半的慢性阻塞性肺病患者在计算机断层扫描中患有肺气肿，这与死亡率增加有关，但慢性阻塞性肺病的药物治疗仅针对气道。动脉粥样硬化多种族研究 (MESA) COPD 研究招募了 327 名参与者来测试肺气肿的内皮假说，该假说认为吸烟相关的肺内皮损伤会导致肺气肿。 MESA COPD 研究证实其主要目标是： 磁共振成像 (MRI) 上的肺微血管血流量 (PMBF) 显着减少所有严重程度的 COPD 和肺气肿；内皮微粒增多，内皮祖细胞减少；外周血单核细胞的基因表达与 PMBF 密切相关。尽管支持内皮假说，但研究结果也可能是由于新近描述的异常缺氧性肺血管收缩 (HPV) 或通气受损导致的残留 HPV 所致。我们还发现，慢性阻塞性肺病和肺气肿（我们称之为肺心病）患者的右心室 (RV) 容积减少。试点数据表明，这种情况与普通人群的全因死亡率有关，并可能导致： 右心室僵硬和轻微的通气障碍。此次更新是 MESA COPD 研究的纵向延续，其中我们的目标是使用氧分压、通气、PMBF 和肺气肿的区域测量，以及逆转 HPV 和治疗过度通货膨胀的干预措施，以及 RV 功能和 MRI 静脉血流量的创新测量来检验以下假设：肺气肿的特点是 PMBF 减少，与 HPV 无关，并且 通气障碍；肺心病与右心室僵硬和胸内压升高有关；肺部非肺气肿区域 PMBF 的减少与五年后局部肺气肿的发展和组织损失有关。该提案的创新方面包括使用具有直接临床相关性的新型 MRI 成像模式、检查新实体肺小病以及对人类肺气肿血管假说的纵向测试。这些目标的确认将创造 COPD 治疗的范式转变，以证明针对肺气肿肺血管系统的现有和新型（例如 EPC/干细胞）疗法的测试是合理的，提供潜在的成像生物标志物以促进此类疗法的早期、短期临床试验，并提出接近和可能治疗肺心病的机制。