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

 描述(由申请人提供)：测定电子烟对年轻人的急性肺毒性对公共卫生具有重大意义。电子烟蒸气含有既定的毒物，预计会对呼吸道和肺微血管造成急性损害，最终导致慢性肺部疾病，目前对这种疾病的有效治疗方法仍然很少。磁共振成像(MRI)和血管成像(MRA)措施是检测和表征电子烟预期的急性肺毒性的有前途的方法。在确定呼吸道毒性方面，超极化氦(3He)增强MRI可能比肺活量(一种全球肺功能指标)更敏感。3He增强MRI已被用于显示肺活量正常的健康人的呼吸缺陷的程度，测量哮喘患者使用支气管扩张剂和乙酰甲胆碱治疗前后的呼吸变化，以及预测COPD患者的肺部住院。与此同时，直到最近，还缺乏对肺血管毒性的非侵入性测量。我们团队开发了一种基于Gd增强MRA的肺微血管血流的创新测量方法，我们发现这种测量在早期慢性阻塞性肺疾病(COPD)和肺气肿中明显异常，并与内皮功能障碍的标志-内皮微粒增加有关。尽管如此，这两种敏感的、非侵入性的、可重复的和可重复的测量方法都从未被用于评估电子烟的毒性。因此，我们提出了一项使用黄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、年轻的成年电子烟使用者3He增强MRI和Gd增强MRA的急性影响。我们假设吸入电子烟蒸气将导致全球和局部通风缺陷的急剧增加，以及全局和局部肺微血管灌注量的急剧下降。这项试点工作将提供经验和数据，以支持随后的资金申请，从而最终确定各种成分的电子烟蒸气的急性毒性(例如，在有和没有电子烟的情况下 有或无慢性肺部疾病(如哮喘)患者的尼古丁)对肺通气量和微血管灌注量的影响。此外，在这个有限的样本中确认我们的假设将提供重要的电子烟肺部毒性的初步证据，为临时监管决定提供参考，并可能生成电子烟危害的生动图像，这些图像可能对普通公众有意义，因此适合用于公共教育活动。

 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.