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

摘要：中国 在过去的十年里，许多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)已成为人们追捧的对象 这是因为人们相信香烟比传统香烟安全得多。此外，吸烟(TS)是 与血管内皮细胞功能障碍相关，主要与TS有关，且呈剂量依赖性 活性氧(ROS)、尼古丁和氧化应激(OS)引发的炎症。当代科学 观点认为OS介导的通路在这些疾病的发病机制中发挥着重要作用，特别是中风。 临床前研究(和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，加重脑缺血和继发性脑损伤。同样，慢性e-Cig蒸发可能会 前驱症状到脑血管损害，促进脑血管疾病，有利于中风的发病和后 缺血性脑损伤，从我们最初的发现来看。电子烟对健康的影响目前尚不清楚， 研究有限，缺乏e-Cigs蒸发液含量的监管指南(各种有害因素 在e-cig蒸气中检测到包括醛、亚硝胺等在内的化合物)已成为关键公众 我们也希望通过这项研究来解决监管方面的担忧。此外，我们和其他人发现TS促进了 并增加患2型糖尿病(2 DM)的风险 致病特征包括脑血管和神经疾病的高风险，如通过产生ROS而中风， 炎症和血脑屏障(BBB)损害。来自我们小组的最新体外研究结果和初步数据， 血脑屏障内皮细胞支持血管生成、氧化和炎症因子的相加释放模式 对高血糖(HG)和/或中风条件的反应，并伴随着暴露于香烟烟雾提取物(CSE)， 提示BBB损伤的常见致病调节因子参与其中。为此，二甲双胍(MF；a 被广泛处方的Firstline抗糖尿病药物)在中风损伤前后被证明可以减轻压力和抑制 炎性反应88.最近的初步数据显示，MF激活了反作用机制， 在血脑屏障水平上大幅降低TS的毒性。这些有益的影响已被证明是由MF介导的 核因子红系相关因子(NRF2)的激活我们的假设是，TS和e-s导致的过度OS- CIGS细胞抗氧化反应系统的失调是与 脑血管毒性与卒中高风险和/或严重程度 在这方面，我们将：1)评估e-Cig蒸发与TS通过一侧的潜在脑血管致病影响 根据监管机构最近发出的调查e-Cig毒性的行动号召，与 2)评估分子机制(以Nrf2/线粒体为重点)驱动TS依赖的损伤 血脑屏障和增强的风险卒中；3)评估二甲双胍预防/减少TS的可行性和有效性 可能是e-Cig汽化导致的血脑屏障损伤和随后的缺血性卒中损伤。这是最重要的 由于长期吸烟对心血管疾病和中风的风险很高，但护理治疗(S)才刚刚开始 根据疾病的临床表现。对于长期吸烟者(包括早期吸烟者，对他们来说， 中风的风险仍然很高)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.