The Effects of a Standardized Research E-Cigarette On The Human Lung: A Clinical Trial With Bronchoscopic Biomarkers

摘要 电子烟(e-cig)的使用正在迅速增加。然而，人们对这种潜在的肺部毒性知之甚少。 与吸烟相关的吸入电子烟的气雾剂。FDA认为对电子烟和电子烟需求的监管权威 数据，以确定如何规范其设计和组成。有可能电子烟雾剂的气雾剂成分 (这些物质的载体、味道和副产品)会在肺部引起炎症反应，但没有直接的 这方面的证据，以及影响的程度(如果有的话)。虽然可能有许多正在进行的 实验室的体外和体内研究，以评估电子烟的暴露和毒性，这些利用间接方法 评估肺部毒性。也有正在进行的人体研究关注电子烟的使用对吸烟的影响。 暴露的相关生物标记物，但这些通常评估肺外的生物体液(例如血液和尿液)。它是 尚不清楚这些研究中的任何一项可能如何与肺毒性相关，例如，靶器官，因此存在关键的 研究差距。为了评估使用电子烟对人体的肺部毒性，我们建议对128名吸烟者进行临床试验。 通过连续支气管镜检查评估肺部炎症反应。为了做到这一点，我们将利用一种非凡的 通过使用新的NIDIA标准化研究电子CIG(SREC)来研究电子CIG毒性的机会。科目 将被随机分配到继续吸烟(对照)，两种电子烟使用条件之一(完成 替代尼古丁SREC或两用并计划减少吸烟)，或完全替代 尼古丁替代疗法(NRT)。每组32名受试者，试验为期5周(为期1周- 在此期间，接下来是4周的实验条件)。主要结果将是肺生物标记物(细胞 计数、细胞因子、呼出的一氧化氮、RNA和microRNA基因表达，以及非靶向代谢组学)。 将采用几种生化措施来评估遵从性。尿液和鼻腔的生物储存库 样本将被创建用于未来的研究，以比较非侵入性生物标记物和肺生物标记物。这个 这项试验的基础设施已经根据FDA和IRB批准的方案建立。这项研究是 意义重大，因为它将侧重于肺部炎症，电子烟使用对肺部的可能影响，以及 用于切换到电子烟或两用，而不是完全停止使用NRT。一旦需要这样的数据， 可能协助FDA对电子烟进行监管，包括尼古丁含量。这项研究具有创新性，使用了 一项使用连续支气管镜检查的临床试验设计，将炎症生物标记物与代谢和 基因表达数据，并使用综合、互补和全面的方法通过多个 组学分析(基因表达--mRNA和miRNA、代谢组学、细胞浸润物和细胞因子水平)。这 这项研究对公共卫生有相当大的影响，因为它将在人类身上提供靶向的实验证据 器官效应。

Abstract The use of electronic cigarettes (e-cigs) is increasing rapidly. Yet, little is known about the potential lung toxicity for inhaling e-cig aerosols relative to smoking. The FDA has deemed regulatory authority over e-cigs and needs data to determine how to regulate their designs and constituents. It is plausible that e-cig aerosol constituents (carriers, flavor, and byproducts of these) induce an inflammatory response in the lung, but there is no direct evidence for this, and what the magnitude of the effect is, if any. While there may be numerous ongoing laboratory in vitro and in vivo studies to assess e-cig exposure and toxicity, these utilize indirect methods for assessing lung toxicity. There also are ongoing human studies that focus on the effect of e-cig use on smoking- related biomarkers of exposure, but these usually assess biofluids outside the lung (e.g., blood and urine). It is unknown how any of these studies may relate to lung toxicity, e.g., the target organ, and thus there is a critical research gap. To assess human lung toxicity from e-cig use, we propose to conduct a clinical trial of 128 smokers to assess inflammatory responses in the lung via serial bronchoscopy. To do this, we will exploit an extraordinary opportunity for study e-cig toxicity by employing the new NIDIA standardized research e-cig (SREC). Subjects will be randomized to continued cigarette smoking (control), one of two e-cig use conditions (complete substitution with the nicotine SREC or dual use with planned smoking reduction), or complete substitution with nicotine replacement therapy (NRT). Each group will be 32 subjects and the trial will be 5 weeks (a 1 week run- in period, followed by 4 weeks of the experimental condition). Primary outcomes will be lung biomarkers (cell counts, cytokines, exhaled nitric oxide, RNA and microRNA gene expression, and untargeted metabolomics). Several biochemical measures to assess compliance will be employed. A biorepository of urine and nasal samples will be created for future studies to compare non-invasive biomarkers with lung biomarkers. The infrastructure for this trial is already established under an FDA- and IRB approved protocol. This study is significant because it will focus on lung inflammation, a plausible effect on the lungs of e-cig use, and the impact for switching to e-cigs or dual use, versus complete cessation with NRT. Such data are needed as soon as possible to assist the FDA in the regulation of e-cigs, including nicotine content. The study is innovative by using a clinical trial design using serial bronchoscopy, incorporating inflammation biomarkers with metabolomic and gene expression data, and uses an integrative, complementary and comprehensive approach through multiple ‘omics assays (gene expression – mRNA and miRNA, metabolomics, cell infiltrates and cytokine levels). This study has considerable public health impact because it will provide experimental evidence in humans of target organ effects.