Functional CT Assessment of Pulmonary Arterial Dysfunction in Smoking Associated Emphysema

吸烟相关肺气肿肺动脉功能障碍的功能 CT 评估

• 批准号: 9016079
• 负责人: ERIC Alfred HOFFMAN
• 金额: $ 71.98万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9016079
• 关键词: Alveolar; Alveolus; Animals; Anti-Inflammatory Agents; Apical; Area; Blood; Blood Vessels; Blood Volume; Blood flow; Breathing; Chronic Obstructive Airway Disease; Cialis; Defense Mechanisms; Dilatation - action; Disease; Edema; Etiology; Exercise; Failure; Floods; Functional disorder; Gases; Genotype; Glass; Heterogeneity; Hour; Human; Hyperoxia; Hypoxia; Image; Inflammation; Inflammatory; Injury; Intervention; Irritants; Lead; Link; Lung; Lung Inflammation; Maps; Measures; Mediating; Nitric Oxide; Outcome; Outcome Assessment; Outcome Study; Oxygen; Pathologic Processes; Patients; Perfusion; Phenotype; Play; Population; Predisposition; Process; Pulmonary Emphysema; Pulmonary Inflammation; Pulmonary function tests; Radiolabeled; Resistance; Resolution; Rest; Role; Series; Shunt Device; Signal Transduction; Smoker; Smoking; Stem cells; Structure of parenchyma of lung; Testing; Therapeutic Intervention; Time; Tissues; Variant; Vascular Diseases; Vascular resistance; Vasodilation; Visual; X-Ray Computed Tomography; airway remodeling; attenuation; base; density; design; expectation; falls; hemodynamics; improved; indexing; injured; insight; lung apex; lung injury; neutrophil; public health relevance; radiotracer; repaired; research study; response; sildenafil; single photon emission computed tomography; smoking cessation; tadalafil; therapeutic target; tool; vasoconstriction

 DESCRIPTION (provided by applicant): Imaging-based metrics have recently played a central role in the quest to identify COPD phenotypes, serving to establish homogeneous sub-populations to aid in genotyping, therapeutic targeting and design and outcomes assessment. Recent findings in both animals and humans have lead us to believe that CT derived perfusion (PBF) and mean transit time (MTT) measures within regionally injured lung parenchyma provide for a functional phenotype of which may be directly tied to the etiology of the pathologic process leading to emphysema in acentrilobular emphysema susceptible subset of the smoking population. The primary hypotheses of the proposal are built around the notion that smokers prone to emphysema have abnormal vasoregulation in that regional hypoxic pulmonary vasoconstriction (HPV) continues despite regional lung injury. This failure to block vasoconstriction alters the repair response and leads to tissue destruction in emphysema susceptible smokers (SS) with abnormal vasoregulation. The normal response to regional hypoxia is to shunt blood towards better- ventilated regions. However, smoking induces small scale, regional infiltrates which in turn lead to local hypoxia, HPV would interfere with defense mechanisms serving to clear the irritant and thus interfere with mechanisms of repair. We have demonstrated that, in SS subjects with normal PFTs but CT evidence of early centriacinar emphysema (CAE), there is an increased heterogeneity of perfusion. This is supportive of the notion that attenuation of vasoconstriction has failed. Further, we have demonstrated a tight correlation between quantitative CT evidence of emphysema with reduced LV filling down to very small amounts of emphysema. We outline a series of experiments seeking to: 1) link increased pulmonary perfusion heterogeneity in SS subjects to the lung's response to alveolar oxygenation; 2) establish that the perfusion heterogeneity is reversible; 3) demonstrate that the response to inflammation and not just inflammation itself is a key factor in the increased heterogeneity and finally; 4) demonstrate that, by alleviating heterogeneous vasoconstriction, parenchymal hyper-density associated with smoking will clear more quickly in association with smoking cessation. With any combination of positive outcomes of this study, we will have provided new insights into disease etiology, serving to provide new targets for disease intervention and providing the tools needed for assessing outcomes.

 描述（由申请人提供）：基于成像的指标最近在识别 COPD 表型的过程中发挥了核心作用，有助于建立同质亚群，以帮助基因分型、治疗目标和设计以及结果评估。人类使我们相信，区域损伤肺实质内的 CT 衍生灌注（PBF）和平均通过时间（MTT）测量提供了功能表型，其可能与肺损伤的病因直接相关。吸烟人群中小叶中心性肺气肿易感人群中导致肺气肿的病理过程 该提案的主要假设是围绕易患肺气肿的吸烟者的血管调节异常这一概念而建立的，因为尽管存在区域性肺损伤，但区域性缺氧性肺血管收缩（HPV）仍然存在。未能阻止血管收缩会改变血管调节异常的肺气肿易感吸烟者（SS）的修复反应并导致组织破坏。缺氧是将血液分流到通风更好的区域，然而，吸烟会引起小范围的局部浸润，进而导致局部缺氧，HPV 会干扰清除刺激物的防御机制，从而干扰修复机制。在 PFT 正常但 CT 证据显示早期中心性肺气肿 (CAE) 的 SS 受试者中，灌注的异质性增加，这支持了灌注衰减的观点。此外，我们还证明了肺气肿的定量 CT 证据与左心室充盈减少至极少量的肺气肿之间存在紧密相关性。我们概述了一系列实验，旨在：1）将 SS 受试者的肺灌注异质性增加与此联系起来。肺对肺泡氧合的反应；2) 确定灌注异质性是可逆的；3) 证明对炎症的反应而不仅仅是炎症本身是异质性增加的关键因素；最后；4）证明，通过减轻异质性血管收缩，与吸烟相关的实质高密度将随着戒烟而更快地消失，通过本研究的积极结果的任何组合，我们将为疾病病因学提供新的见解，旨在为疾病干预提供新的目标，并提供评估结果所需​​的工具。