Testing Tobacco Smoke and e-Cigarette Toxicity at the Blood-Brain Barrier

摘要： 在过去的十年中，许多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）已成为受欢迎的 因为他们相信它们比传统香烟更安全。此外，吸烟（TS） 以主要与TS相关的病因和剂量依赖性方式与血管内皮功能障碍相关 活性氧簇（ROS）、尼古丁和氧化应激（OS）驱动的炎症的含量。当前科学 有观点认为OS介导的途径在这些疾病尤其是中风的发病机制中起主要作用。 临床前研究（以及本文提供的初步数据）表明，尼古丁（电子液体的主要成分） 可引起OS、脑缺血加重和继发性脑损伤。同样，慢性电子烟可能是 前驱期至脑血管损伤，并促进有利于中风发作和中风后的脑血管状况。 缺血性脑损伤，这是我们最初的发现。电子烟对健康的影响目前尚不清楚， 有限的研究和缺乏监管准则的内容vaping解决方案的电子烟（各种有害的 在电子烟蒸气中检测到包括醛、亚硝胺等的化合物）已经成为公众的批评， 和监管方面的问题，我们也想通过这项研究来解决。此外，我们和其他人已经发现，TS促进 葡萄糖耐受不良，增加患2型糖尿病（2DM）的风险， 致病特征包括通过ROS产生的脑血管和神经系统疾病如中风的高风险， 炎症和血脑屏障（BBB）损伤。最近的体外研究结果和我们小组的初步数据， 支持BBB内皮细胞的血管生成、氧化和炎症因子的附加释放模式， 对高血糖症（HG）和/或中风状况的反应，伴随着对香烟烟雾提取物（CSE）的舒适暴露， 从而提示BBB损伤的常见致病调节剂的参与。为此，二甲双胍（MF; a 广泛使用的一线抗糖尿病药物）在中风损伤前后已经显示出减少压力和抑制 炎症反应88.最近的初步数据显示，MF激活了对抗机制， 在BBB水平显著降低TS毒性。这些有益的作用已被证明是由MF介导的 核因子红细胞2相关因子（Nrf 2）的活化51.我们的假设是，TS和e- 细胞抗氧化反应系统的调节异常是前驱体与 脑血管毒性和卒中风险和/或严重程度增加 在这方面，我们将：1）通过侧面评估电子烟vaping与TS的潜在脑血管致病影响 根据最近的行动呼吁，由监管机构和监管机构调查电子烟毒性， 外科医生; 2）评估驱动TS依赖性损伤的分子机制（Nrf 2/线粒体聚焦）， BBB和卒中风险增加; 3）评估二甲双胍（MF）预防/减少TS的可行性和有效性 以及可能的电子烟雾化诱导的BBB损伤和随后的缺血性中风损伤。这是最重要的 由于长期吸烟具有心血管疾病（CVD）和中风高风险， 根据疾病的临床表现。对于长期吸烟者（包括早期吸烟者， 中风仍然很高），没有可用的预防选择。

Abstract:  In the past decade a number of 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 the sought-after product due to the belief that they are much safer than traditional cigarettes. Moreover, tobacco smoking (TS) is 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 (and preliminary data presented herein) have shown that nicotine (the principal e-liquid's ingredient) can 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 that favor the onset of stroke and post- ischemic brain injury, suggested by our initial findings. The health impact of e-Cig vaping is currently unknown and the limited research and dearth of regulatory guidelines for the content of the vaping solution for e-Cigs (various harmful compounds including aldehydes, nitrosamines etc. have been detected in the e-Cig vapors) has become a critical public and regulatory concern we also want to address with this research. Further, we and others have found that TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Recent in vitro findings and preliminary data from our group, supports an additive release pattern of angiogenic, oxidative and inflammatory factors by BBB endothelial cells in response to hyperglycemia (HG) and/or stroke conditions with comcomitant exposure to cigarette smoke extracts (CSE), thus suggesting the involvement of common pathogenic modulators of BBB impairment. To this end, metformin (MF; a widely prescribed, firstline anti-diabetic drug) before and after stroke injury has been shown to reduces stress and inhibits inflammatory responses 88. Recent preliminary data revealed that MF activates counteractive mechanisms which drastically reduce TS toxicity at the level of the BBB. These beneficial effects have been shown to be mediated by MF activation of nuclear factor erythroid 2-related factor (Nrf2) 51. Our hypothesis is that excessive OS caused by TS and e- Cigs dysregulation of the cellular antioxidant response system is the linking underling mechanism prodromal to cerebrovascular toxicity and highten risk and/or severity of stroke In this respect we will: 1) Assess the potential cerebrovascular pathogenic impact of e-Cig vaping vs. TS through a side by side comparative study as per a recent call to action to investigate e-Cig toxicity by the regulatory agency and the Surgeon General; 2) Assess the molecular mechanisms (Nrf2/mitochondrial focused) driving TS-dependent impairment of the BBB and enhanced risk stroke and 3) Assess the viability and effectiveness of metformin (MF) to prevent/reduce TS and possibly e-Cig vaping-induced BBB damage and subsequent ischemic stroke injury. This is of outmost importance since chronic smoking carry high risks for cardiovascular diseases (CVD) and stroke but care treatment(s) only begins upon clinical manifestation of a disease. For chronic smokers (including early stage former smokers for whom the risk of stroke is still very high) there are no prophylactic options available.