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 尤其是青少年。电子尼古丁输送系统或电子烟（电子烟）已成为感官 由于相信它们比传统香烟更安全。而且，吸烟（TS）是 与TS相关的致病和剂量依赖性方式，与血管内皮功能障碍相关 活性氧（ROS），尼古丁和氧化应激（OS）驱动的炎症的含量。当前的科学 意见认为OS介导的途径在这些疾病的发病机理中发挥重要作用，尤其是中风。 临床前研究（此处提供的初步数据）表明尼古丁（主要的电子液体成分） 可能导致OS，大脑缺血的加剧和继发性脑损伤。同样，慢性电子烟烟可能是 脑血管损伤前驱物质，并促进脑血管疾病，有利于中风和脑血管疾病 缺血性脑损伤，这是我们最初的发现。电子烟烟的健康影响目前尚不清楚，并且 对电子烟的VAPING解决方案含量的监管指南的研究和死亡有限（各种有害） 在电子烟蒸气中检测到包括醛，亚硝胺等在内的化合物已成为关键的公众 和监管问题，我们也想解决这项研究。此外，我们和其他人发现TS促进 葡萄糖intlerance并增加患与其他共享其他类型糖尿病（2DM）的风险 致病性状，包括脑血管和神经系统疾病的高风险，例如通过ROS产生， 炎症和血脑屏障（BBB）障碍。我们小组的最新体外发现和初步数据， 支持BBB内皮细胞中血管生成，氧化和炎症因子的额外释放模式 对高血糖（HG）和/或中风条件的反应，与香烟烟雾提取物（CSE）相结合， 因此表明BBB损伤的常见致病调节剂参与。为此，二甲双胍（MF; a 已广泛处方，第一行抗糖尿病药）在中风损伤之前和之后已显示可减轻压力并抑制 炎症反应88。最近的初步数据表明，MF激活了反活性机制 大大降低了BBB水平的TS毒性。这些有益效应已被证明是由MF介导的 核因子红细胞2相关因子的激活（NRF2）51。我们的假设是由TS和E-引起的多余OS 细胞抗氧化剂反应系统的CIGS失调是连接的底部机理 脑血管毒性和中风的风险和/或严重程度 在这方面，我们将：1）评估电子烟蒸发与TS的潜在脑血管致病影响 根据最近的呼吁调查监管机构和调查电子烟毒性的呼吁，监管机构和 外科医生； 2）评估分子机制（NRF2/线粒体集中）驱动TS依赖性损害的分子机制 BBB和增强风险中风和3）评估二甲双胍（MF）预防/减少TS的生存能力和有效性 并且可能会引起电子烟诱导的BBB损伤和随后的缺血性中风损伤。这至关重要 由于慢性吸烟具有心血管疾病（CVD）和中风的高风险，但护理治疗仅开始 疾病的临床表现。对于长期吸烟者（包括早期阶段的前吸烟者 中风仍然很高）没有可用的预防选择。