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（由适用提供）：基于成像的指标最近在识别COPD表型的寻求中发挥了核心作用，以建立同质的亚种群，以帮助进行基因分型，治疗性靶向和设计以及结果评估。动物和人类的最新发现使我们相信，CT衍生的灌注（PBF）和平均过境时间（MTT）措施在区域损伤的肺实质中提供了一种功能性表型，其功能表型可能直接与病理学的病因有关，导致浓度性无脑症状症状的病理学，导致症状症状症状的症状，并抑制了吸烟量的吸烟人群。该提案的主要假设是围绕着吸烟者容易出现的肺气肿的观念，尽管区域缺氧肺动脉加索（HPV）仍继续进行，但尽管有区域肺损伤，但仍有异常的血管调节。这种无法阻塞的血管收缩会改变维修反应，并导致肺气肿易感吸烟者（SS）的组织破坏，并导致血管调节异常。对区域缺氧的正常反应是将血液分流到更偏见的区域。但是，吸烟会诱导小规模，区域浸润，从而导致局部缺氧，HPV会干扰用于清除刺激物并因此干扰修复机制的防御机制。我们已经证明，在具有正常PFT的SS受试者中，但CT的证据表明了早期Centricinar肺气肿（CAE），灌注的异质性增加了。这支持了血管收缩失败的衰减的观念。此外，我们已经证明了肺气肿的定量CT证据之间存在密切的相关性，而LV降低至少量肺气肿。我们概述了一系列寻求：1）SS受检查中肺部灌注异质性增加的实验，与肺对所有动物氧合的反应； 2）确定灌注异质性是可逆的； 3）证明对感染的反应，而不仅仅是感染本身是异质性增加的关键因素； 4）证明，通过减轻异质血管收缩，与戒烟相关的副群体高密度将更快地清楚地清楚。通过本研究的积极结果的任何结合，我们将提供有关疾病病因的新见解，为疾病干预提供新的目标，并提供评估结果所需​​的工具。