Functional CT Assessment of Pulmonary Arterial Dysfunction in Smoking Associated Emphysema

 描述(由申请人提供)：基于成像的指标最近在寻找COPD表型方面发挥了核心作用，有助于建立同质的亚群，以帮助进行基因分型、治疗靶向以及设计和结果评估。最近在动物和人类中的发现使我们相信，在局部损伤的肺实质内，CT衍生的灌注(PBF)和平均通过时间(MTT)测量提供了一种功能表型，其可能与导致吸烟人群中非小叶肺气肿易感亚群的病理过程的病因学直接相关。该提案的主要假设是基于这样一个概念，即易患肺气肿的吸烟者具有异常的血管调节，因为尽管局部肺损伤，但局部缺氧性肺血管收缩(HPV)仍在继续。这种不能阻止血管收缩的失败改变了修复反应，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，吸烟会诱导小范围、区域性的浸润物，进而导致局部缺氧，HPV会干扰起清除刺激物作用的防御机制，从而干扰修复机制。我们已经证明，在PFTs正常但CT证据为早期向心性肺气肿(CAE)的SS受试者中，血流灌注的不均一性增加。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充盈减少到非常少量的肺气肿之间存在密切的相关性。我们概述了一系列实验，试图：1)将SS受试者肺灌流异质性增加与肺对肺泡充氧的反应联系起来；2)确定灌流异质性是可逆的；3)证明对炎症的反应而不仅仅是炎症本身是导致异质性增加的关键因素；最后，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更快地消失。结合这项研究的任何积极结果，我们将为疾病病因提供新的见解，为疾病干预提供新的目标，并提供评估结果所需的工具。

 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.