Blood and Brain Based Biomarkers of Injury to Assess the Cerebrovascular Impact of Emerging Alternatives to Classic Cigarette Products

摘要： 在过去的十年里，几种替代蒸发产品已经投放市场，迅速赢得了成年人的消费者 尤其是青少年。电子尼古丁传递系统或电子烟(e-Cigs)已变得广泛传播 在吸烟者和以前的不吸烟者中都是如此，因为他们相信香烟比传统香烟安全得多。其中 这些JUUL已经成为包括中学生在内的年轻人的抢手产品。更重要的是，它很好 已证实吸烟(TS)与血管内皮功能障碍的病因和剂量有关 依赖方式主要与TS中的活性氧(ROS)、尼古丁和氧化应激有关 (OS)驱动的炎症。目前的科学观点认为，OS介导的途径在 这些疾病的发病机制，尤指中风。临床前研究也表明，尼古丁(主要的e- 电子烟中使用的液体成分)也会导致OS，加重脑缺血和继发性脑损伤。 同样，慢性e-Cig蒸发可能是脑血管损伤的前兆，并促进脑血管 有利于中风发作和脑缺血后损伤恶化的条件。与以下各项相关的健康影响 慢性e-Cig蒸发在很大程度上是未知的，特别是关于脑血管系统。它们的广泛使用 替代产品强烈要求进行调查研究，以确定其对健康的真正影响，以及更严格的 关于蒸发溶液(电子液体)含量的监管指南。我们新的初步数据也表明 对这些产品的性别敏感的可能性。因此，针对方案的范围和研究 这项呼吁采取行动调查电子CIG对健康的影响和毒性的目标由FDA烟草中心发布 产品基于我们实验室的大量已发表数据和初步数据，我们提出以下建议： 1)评估e-Cig蒸发和聚令与TS暴露对脑血管的影响，并制定一组潜在的 用于确定这些产品危害的生物标记物。这些研究的前提是进行比较性研究 E-Cigs和Juul与TS对血脑屏障的危害或毒性。这包括评估不同电子液体的影响。 关于尼古丁含量的配方以及用于产生蒸汽的盘管热量的影响。 2)在体内评估和验证慢性暴露于e-Cigs和JUUL与TS对中风风险的影响， 继发性脑损伤和缺血后神经损伤。这些研究的前提建立在 最新的临床发现和我们最近公布的数据表明，与TS相似，长期接触e-Cigs会促进 脑血管炎症、中风和加重脑缺血后继发性脑损伤。也要解决这样一种可能性 对于特定性别的敏感性/风险和结果，我们将使用雄性和雌性小鼠的混合性别种群。 总体而言，我们将比较吸烟和电子烟(包括含有不同成分的电子液体)的影响 尼古丁浓度和蒸发电子液体的温度设置)对脑血管损伤的影响。我们的研究将 特别关注它们对中风风险和结局的影响，从基于大脑和血液的生物标记物中确定。

ABSTRACT: In the past decade several alternative vaping products have hit the market, rapidly gaining consumers among adults and, especially, adolescents. Electronic nicotine delivery systems or e-cigarettes (e-Cigs) have become wide spread among both smokers and former non-smokers due to the belief that they are much safer than traditional cigarettes. Among them JUULs have become the sought-after product among youth including middle schoolers. Moreover, it is well established that tobacco smoking (TS) has been associated with vascular endothelial dysfunction in a causative and dose dependent manner primarily related to the TS content of reactive oxygen species (ROS), nicotine, and oxidative stress (OS) -driven inflammation. Current scientific opinion considers OS-mediated pathways to play a major role in the pathogenesis of these disorders, especially stroke. Preclinical studies have also shown that nicotine (the principal e- liquid's ingredient used in e-cigarettes) can also cause OS, exacerbation of cerebral ischemia and secondary brain injury. Likewise, chronic e-Cig vaping could be prodromal to cerebrovascular impairment and promote cerebrovascular conditions favoring the onset of stroke and worsening post-ischemic brain injury. The health impact associated with chronic e-Cig vaping is largely unknown especially concerning the cerebrovascular system. Wide spread use of these alternative products strongly calls for investigative studies to determine their real health impact as well as more stringent regulatory guidelines concerning the content of the vaping solutions (e-liquids). Our new preliminary data also suggests the possibility for gender specific sensitivities to these products. Thus, in response to the program scope and research objectives of this call for action to investigate e-Cig health effects and toxicity issued by the FDA Center for Tobacco Products Based and based on the substantial published and preliminary data from our Labs we propose the following: 1) Assess the cerebrovascular impact of e-Cig vaping and Juuling vs. TS exposure and develop a panel of potential biomarkers to determine harm of these products. The premise of these studies is to comparatively investigate side by side the harm or toxicity of e-Cigs and JUUL vs. TS on the BBB. This includes assessing the impact of different e-liquid formulations in respect to the nicotine content as well as impact of the coil heat used to generate the vapor. 2) Evaluate and validate in vivo the impact of chronic exposure to e-Cigs and JUULs vs. TS on the risk of stroke, secondary brain damage, and post-ischemic neurological impairments. The premise for these studies builds upon the latest clinical findings and our recent published data suggesting that similarly to TS, chronic e-Cigs exposure promotes cerebrovascular inflammation, stroke, and worsen post-ischemic secondary brain injuries. To also address the possibility for gender specific sensitivities/risks and outcomes we will use a mixed gender population of male and female mice. Overall, we will compare the impact of tobacco smoking and e-Cig vaping (including e-liquids containing different nicotine concentrations and temperature settings used to vaporize the e-liquid) on brain vascular damage. Our study will focus specifically on their impact on stroke risk and outcome, ascertained from brain and blood based biomarkers.