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）：最近，基于成像的指标在识别COPD表型的探索中发挥了核心作用，用于建立同质亚群，以帮助进行基因分型、治疗靶向和设计以及结局评估。最近在动物和人类的研究结果使我们相信，CT衍生灌注（PBF）和平均通过时间（MTT）的措施，在局部损伤的肺实质提供了一个功能表型，可能直接与病因的病理过程，导致肺气肿的无小叶肺气肿易感亚组的吸烟人群。该提案的主要假设是建立在这样一个概念上的，即容易患肺气肿的吸烟者具有异常的血管调节，尽管局部肺损伤，但局部缺氧性肺血管收缩（HPV）仍在继续。这种不能阻断血管收缩的情况改变了修复反应，并导致血管调节异常的肺气肿易感吸烟者（SS）的组织破坏。对局部缺氧的正常反应是将血液分流到通风较好的区域。然而，吸烟诱导小规模的区域浸润，这反过来又导致局部缺氧，HPV会干扰用于清除刺激物的防御机制，从而干扰修复机制。我们已经证明，在SS受试者与正常的PFT，但CT证据的早期中央腺泡肺气肿（CAE），有一个增加的异质性灌注。这支持了血管收缩减弱失败的观点。此外，我们已经证明了肺气肿的定量CT证据与LV充盈减少至非常少量的肺气肿之间的紧密相关性。我们概述了一系列实验，旨在：1）将SS受试者中肺灌注异质性增加与肺对肺泡氧合的反应联系起来; 2）建立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; 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在戒烟后更快地清除。通过本研究的任何积极结果的组合，我们将为疾病病因学提供新的见解，为疾病干预提供新的靶点，并提供评估结果所需的工具。