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

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是全球和美国的第三大死亡原因。超过一半的COPD患者在计算机断层扫描上患有肺气肿，这与死亡率增加有关，但COPD的药物治疗仅针对气道。多种族动脉粥样硬化研究（梅萨）COPD研究招募了327名参与者来测试肺气肿的内皮假设，该假设认为吸烟相关的肺内皮损伤有助于肺气肿。梅萨COPD研究证实了其主要目的：磁共振成像（MRI）上的肺微血管血流量（PMBF）显著降低;所有严重程度的COPD和肺气肿;内皮微粒增加，内皮祖细胞减少;外周血单核细胞中的基因表达与PMBF密切相关。虽然支持内皮假说，研究结果也可能是由于新描述的异常缺氧性肺血管收缩（HPV）或残留的HPV从受损的通气。我们还发现COPD和肺气肿患者的右心室（RV）容量减少，我们称之为肺心病。这种情况与一般人群的全因死亡率有关，试点数据表明， 右心室僵硬和轻微的痉挛性损伤该更新是梅萨COPD研究的纵向延续，在该研究中，我们的目标是使用氧分压、通气、PMBF和肺气肿的区域测量，沿着逆转HPV和治疗过度充气的干预措施，以及RV功能和MRI上静脉血流量的创新测量，以测试以下假设：肺气肿的特征是PMBF降低，与HPV和呼吸障碍无关;小肺心病与RV僵硬和胸内压升高相关;肺的非肺气肿区域的PMBF降低与5年时肺气肿和组织损失的局部发展相关。这项建议的创新方面包括使用新的MRI成像模式的直接临床相关性，检查一个新的实体，肺心病小，和纵向测试的血管假说肺气肿在人类。这些目标的确认将在COPD治疗中创造一个范式转变，以证明现有和新的（例如，EPC/干细胞）治疗靶向肺气肿的肺血管，提供了一个潜在的成像生物标志物，以促进早期阶段，短期临床试验的这种疗法，并提出了机制，以接近和可能治疗肺心病小。

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.