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

通过血脑屏障测试烟草烟雾和电子烟的毒性

• 批准号: 9918300
• 负责人: Thomas J Abbruscato
• 金额: $ 38.25万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918300
• 关键词: Address; Adolescent; Adult; Aldehydes; Antidiabetic Drugs; Antioxidants; Attenuated; Automobile Driving; Belief; Blood - brain barrier anatomy; Brain; Brain Injuries; Cardiovascular system; Caring; Cerebral Ischemia; Cerebrovascular Disorders; Cerebrovascular system; Chronic; Cigarette; Clinical; Comparative Study; Data; Development; Disease; Dose; Edema; Effectiveness; Electronic Nicotine Delivery Systems; Electronic cigarette; Endothelial Cells; Evaluation; Female; Funding; Generations; Glucose Intolerance; Guidelines; Health; Hyperglycemia; Impairment; In Vitro; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Link; Measurement; Mediating; Metformin; Methodology; Mitochondria; Molecular; Molecular Target; Mus; Neurologic; Neurons; Nicotine; Nitrosamines; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Play; Positioning Attribute; Proteins; Public Health; Reactive Oxygen Species; Reporting; Research; Risk; Role; Safety; Severities; Side; Smoker; Smoking; Stress; Stroke; Surgeon; System; Testing; Therapeutic; Time; Tobacco smoke; Tobacco smoking behavior; Toxic effect; Toxicology; Youth; base; blood-based biomarker; cardiovascular disorder risk; cerebrovascular; comparative; e-cigarette aerosols; electronic cigarette use; electronic liquid; exposure to cigarette smoke; high risk; in vivo; ischemic injury; male; mortality; nervous system disorder; neuroprotection; neurovascular unit; nuclear factor-erythroid 2; post stroke; preclinical study; prevent; prophylactic; response; restoration; smoking addiction; smoking cessation; stroke risk; stroke-like outcome; tobacco exposure; trait; vaper; vaping; vascular endothelial dysfunction; young adult

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.

抽象的： 在过去的十年中，许多替代电子烟产品进入市场，迅速赢得了成年人的消费者 尤其是青少年，电子尼古丁输送系统或电子烟（e-Cigs）已成为炙手可热的产品。 因为人们相信它们比传统香烟安全得多。此外，吸烟 (TS) 也很危险。 与血管内皮功能障碍相关，其因果关系和剂量依赖性方式主要与 TS 有关 活性氧（ROS）、尼古丁和氧化应激（OS）驱动的炎症的含量。 观点认为操作系统介导的途径在这些疾病（尤其是中风）的发病机制中发挥着重要作用。 临床前研究（以及本文提供的初步数据）表明尼古丁（电子烟油的主要成分） 可能会导致 OS、脑缺血加剧和继发性脑损伤。同样，长期吸电子烟也可能会导致脑损伤。 脑血管损伤的前驱症状，并促进有利于中风发作和卒中后的脑血管状况 我们的初步研究结果表明，电子烟对健康的影响目前尚不清楚。 对电子烟解决方案内容的研究有限且缺乏监管指南（各种有害物质） 电子烟蒸气中检测到的醛类、亚硝胺等化合物）已成为公众关注的焦点 我们还希望通过这项研究解决监管问题。此外，我们和其他人发现 TS 可以促进。 葡萄糖不耐症并增加患 2 型糖尿病 (2DM) 的风险，2 型糖尿病与其他糖尿病有共同之处 致病特征包括通过 ROS 产生导致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。我们小组的最新体外研究结果和初步数据， 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（HG）和/或中风状况的反应，同时暴露于香烟烟雾提取物（CSE）， 因此表明 BBB 损伤的常见致病调节剂参与了为此目的，二甲双胍（MF；a）。 中风损伤前后广泛使用的一线抗糖尿病药物）已被证明可以减轻压力并抑制 炎症反应 88. 最近的初步数据显示，MF 激活反作用机制， 显着降低 BBB 水平的 TS 毒性。这些有益作用已被证明是由 MF 介导的。 核因子红细胞 2 相关因子 (Nrf2) 的激活51。我们的假设是 TS 和 e- 引起的过度 OS Cigs 细胞抗氧化反应系统失调是前驱期的潜在机制 脑血管毒性和增加中风的风险和/或严重程度 在这方面，我们将： 1) 通过侧面评估电子烟与 TS 的潜在脑血管致病影响 根据监管机构和监管机构最近呼吁采取行动调查电子烟毒性的并行比较研究 外科医生；2) 评估驱动 TS 依赖性损伤的分子机制（以 Nrf2/线粒体为重点） BBB 和增加的中风风险，以及 3) 评估二甲双胍 (MF) 预防/减少 TS 的可行性和有效性 电子烟可能引起血脑屏障损伤和随后的缺血性中风损伤，这是最重要的。 因为长期吸烟会带来心血管疾病 (CVD) 和中风的高风险，但护理治疗才刚刚开始 对于长期吸烟者（包括早期吸烟者，其有患病风险）。 中风的发病率仍然很高），没有可用的预防措施。