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，几种替代电子烟产品已经进入市场，迅速吸引了成年人的消费者。 尤其是青少年。电子尼古丁输送系统或电子烟（e-cigarettes，e-cigarettes）已经广泛传播。 在吸烟者和以前的非吸烟者中，由于相信它们比传统香烟安全得多。之间 这些JUUL已经成为包括中学生在内的年轻人追捧的产品。而且， 确定吸烟（TS）与血管内皮功能障碍的病因和剂量相关， 依赖方式主要与活性氧（ROS）、尼古丁和氧化应激的TS含量有关 (OS)- 驱动的炎症。目前的科学观点认为OS介导的途径在疾病的发生中起着重要作用。 这些疾病的发病机制，尤其是中风。临床前研究还表明，尼古丁（主要的电子 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，长期电子烟可能是脑血管损伤的前兆， 有利于中风发作和缺血后脑损伤恶化的条件。与之相关的健康影响 长期电子烟吸电子烟在很大程度上是未知的，尤其是关于脑血管系统。广泛使用这些 替代产品强烈要求进行调查研究，以确定其真实的健康影响， 关于电子烟溶液（电子液体）含量的监管指南。我们新的初步数据还表明 对这些产品的性别敏感性的可能性。因此，针对方案范围和研究 FDA烟草中心发布的这一呼吁的目的是调查电子烟的健康影响和毒性 产品基于我们实验室的大量已发表和初步数据，我们提出以下建议： 1)评估电子烟vaping和Juuling与TS暴露对脑血管的影响，并开发一个潜在的小组 生物标志物，以确定这些产品的危害。这些研究的前提是并排比较研究 e-BOS和JUUL vs. TS对BBB的危害或毒性。这包括评估不同电子液体的影响 在尼古丁含量以及用于产生蒸汽的线圈热量的影响方面，对配方进行了改进。 2)在体内评价和验证长期暴露于e-BOS和JUUL与TS对卒中风险的影响， 继发性脑损伤和缺血后神经损伤。这些研究的前提是建立在 最新的临床研究结果和我们最近发表的数据表明，与TS相似，长期暴露于e-sos会促进 脑血管炎症、中风和加重缺血后继发性脑损伤。为了解决 对于性别特异性敏感性/风险和结果，我们将使用雄性和雌性小鼠的混合性别群体。 总体而言，我们将比较吸烟和电子烟vaping（包括含有不同成分的电子液体）的影响。 尼古丁浓度和用于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果的影响，从大脑和血液的生物标志物中确定。

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.