Ventilation and Pulmonary Endothelium Toxicities (VaPE-Tox) of E-cigarettes: A Randomized Crossover Pilot Study

 描述（由申请人提供）：确定电子烟在年轻人中的急性肺毒性具有重大的公共卫生意义。电子烟蒸汽含有既定的有毒物质，预计可能会对气道和肺微血管造成急性损伤，最终导致慢性肺部疾病的发展，对此几乎没有有效的治疗方法。 磁共振成像（MRI）和血管造影（MRA）测量是检测和表征电子烟预期急性肺毒性的有前途的方法。超极化氦（3 He）增强MRI可能比肺功能测定法（一种整体肺功能测量）更敏感，用于确定气道毒性。3 He增强MRI已用于显示肺功能正常的健康人的通气缺陷程度;测量支气管扩张剂和乙酰甲胆碱激发前后哮喘患者的通气变化;并预测COPD患者的肺部住院治疗。同时，直到最近，肺血管毒性的非侵入性措施仍然缺乏。我们的小组开发了一种创新的测量肺微血管血流的钆（Gd）增强MRA，我们发现这是显着异常的早期慢性阻塞性肺疾病（COPD）和肺气肿，并与增加内皮微粒，内皮功能障碍的标志物。尽管如此，这些敏感的、非侵入性的、可重复的和可再现的测量方法都没有被用来评估电子烟的毒性。 因此，我们提出了一项使用金标准随机交叉设计的试点研究，以测试标准化电子烟暴露对10名健康年轻成年电子烟使用者的3 He增强MRI和Gd增强MRA的急性影响。我们假设电子烟蒸汽吸入将导致整体和区域通气缺陷的急性增加以及整体和区域肺微血管灌注的急性减少。 这项试点工作将提供经验和数据，以支持随后的资助申请，以明确确定各种成分的电子烟蒸气的急性毒性（例如，具有和不具有 尼古丁，有和没有调味剂）在患有和没有慢性肺病的人中（例如，哮喘）对肺通气和微血管灌注的影响。此外，在这个适度的样本中证实我们的假设将提供电子烟肺毒性的重要初步证据，以告知临时监管决定，并可能生成电子烟危害的活体图像，这些图像可能对公众有意义，因此适合用于公众教育活动。

 DESCRIPTION (provided by applicant): Determination of the acute pulmonary toxicities of e-cigarettes in young adults is of major public health importance. E-cigarette vapor contains established toxicants which may be anticipated to cause acute damage to the airways and the pulmonary microvasculature resulting in the eventual development of chronic lung disease, for which there remain few effective therapies. Magnetic resonance imaging (MRI) and angiography (MRA) measures are promising approaches to detecting and characterizing the anticipated acute pulmonary toxicities of e-cigarettes. Hyperpolarized helium (3He)-enhanced MRI may be more sensitive than spirometry, a global lung function measure, for determination of airway toxicities. 3He-enhanced MRI has been used to demonstrate the extent of ventilation defects in healthy persons with normal spirometry; to measure ventilation changes in asthmatics pre- and post-challenge with bronchodilators and methacholine; and to predict pulmonary hospitalizations in persons with COPD. Meanwhile, until recently, non-invasive measures of pulmonary vascular toxicities were lacking. Our group developed an innovative measure of pulmonary microvascular blood flow on gadolinium (Gd)-enhanced MRA, which we found to be markedly abnormal in early chronic obstructive pulmonary disease (COPD) and emphysema, and to be associated with increased endothelial microparticles, a marker of endothelial dysfunction. Nonetheless, neither of these sensitive, non-invasive, repeatable, and reproducible measures has ever been used to assess e-cigarette toxicities. We therefore propose a pilot study using a gold-standard randomized crossover design to test the acute effects of a standardized e-cigarette exposure on 3He-enhanced MRI and Gd-enhanced MRA in ten healthy, young adult e-cigarette users. We hypothesize that e-cigarette vapor inhalation will result in an acute increase in global and regional ventilation defects and an acute decrease in global and regional pulmonary microvascular perfusion. This pilot work will provide the experience and data to support subsequent funding applications powered to definitively establish the acute toxicities of e-cigarette vapor of various compositions (e.g., with and without nicotine, with and without flavoring) in persons with and without chronic lung diseases (e.g., asthma) on pulmonary ventilation and microvascular perfusion. Furthermore, confirmation of our hypotheses in this modest sample would provide important preliminary evidence of e-cigarette pulmonary toxicities to inform interim regulatory decisions, as well as potentially generating vivi images of e-cigarette harms that may be meaningful to the general public and therefore suitable for use in public education campaigns.