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

标准化研究电子烟对人肺的影响：支气管镜生物标志物的临床试验

• 批准号: 9476111
• 负责人: Peter G. Shields
• 金额: $ 63.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9476111
• 关键词: Address; Aerosols; Affect; Animals; Biochemical; Biological Assay; Biological Markers; Blood; Breathing; Bronchoscopy; Cell Count; Cell Culture Techniques; Cells; Chemicals; Chronic Obstructive Airway Disease; Cigarette; Clinical Trials; Clinical Trials Design; Cotinine; Cross-Sectional Studies; Data; Decision Making; Electronic cigarette; Exhalation; Feasibility Studies; Flavoring; Funding; Future; Gene Expression; Goals; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intention; Irrigation; Laboratories; Laboratory Study; Lung; Lung Inflammation; Lung diseases; Malignant neoplasm of lung; Marketing; Measures; Messenger RNA; Methods; MicroRNAs; Nasal Epithelium; National Institute of Drug Abuse; Nicotine; Nitric Oxide; Nose; Organ; Participant; Pathogenesis; Pathway interactions; Peer Review; Pilot Projects; Protocols documentation; Public Health; Pulmonary Inflammation; Quality Control; RNA; Randomized; Randomized Clinical Trials; Regulation; Research; Research Infrastructure; Risk Reduction; Running; Safety; Sampling; Science; Smoke; Smoker; Smoking; Standardization; Surrogate Markers; Time; Tobacco; Toxic effect; Toxicant exposure; United States Food and Drug Administration; United States National Institutes of Health; Universities; Urine; authority; biobank; cigarette smoking; cigarette smoking; cytokine; data integration; design; environmental tobacco smoke exposure; human data; in vivo; innovation; mRNA Expression; metabolomics; multiple omics; never smoker; nicotine replacement; primary outcome; smoking cessation; treatment effect; urinary; voltage

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.

摘要 电子烟（e-cigs）的使用正在迅速增加。然而，对潜在的肺毒性知之甚少 用于吸入相对于吸烟的电子烟气溶胶。FDA认为电子烟的监管机构和需求 数据，以确定如何规范其设计和成分。电子烟的气溶胶成分 （载体，香料和这些副产物）诱导肺部炎症反应，但没有直接的 这一点的证据，以及影响的大小，如果有的话。虽然可能有许多正在进行的 实验室体外和体内研究评估电子烟暴露和毒性，这些研究利用间接方法， 评估肺毒性。也有正在进行的人体研究，重点是电子烟对吸烟的影响- 相关的暴露生物标志物，但这些通常评估肺外的生物流体（例如，血液和尿液）。是 尚不清楚这些研究与肺毒性的关系，例如，靶器官，因此有一个关键的 研究差距。为了评估使用电子烟对人类肺部的毒性，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，我们将利用一个非凡的 通过采用新的NIDA标准化研究电子烟（SREC）研究电子烟毒性的机会。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） 用尼古丁SREC替代或计划减少吸烟的双重用途），或完全替代 尼古丁替代疗法（NRT）每组将有32名受试者，试验将持续5周（1周运行- 阶段，随后是4周的实验条件）。主要结果将是肺生物标志物（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）。 将采用几种生物化学措施来评估依从性。尿液和鼻腔的生物储存库 将为未来的研究创建样本，以比较非侵入性生物标志物与肺生物标志物。的 本试验的基础设施已根据FDA和IRB批准的方案建立。本研究 重要的是，它将重点关注肺部炎症，电子烟使用对肺部的合理影响，以及 转换为电子烟或两用，而不是完全停止使用NRT。这些数据需要尽快， 这可能有助于FDA监管电子烟，包括尼古丁含量。本研究的创新之处在于， 使用连续支气管镜检查的临床试验设计，将炎症生物标志物与代谢组学和 基因表达数据，并通过多种方法使用综合，互补和全面的方法， 组学分析（基因表达- mRNA和miRNA、代谢组学、细胞浸润和细胞因子水平）。这 这项研究具有相当大的公共卫生影响，因为它将为人类提供目标的实验证据。 器官效应。