Testing tobacco smoke toxicity at the blood-brain barrier

通过血脑屏障测试烟草烟雾毒性

基本信息

批准号：
8434944
负责人：
Luca Cucullo
金额：
$ 28.51万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434944
关键词：
Accounting Address Advertising Affect Area Atherosclerosis Awareness Blood - brain barrier anatomy Blood Cells Blood Platelets Blood Substitutes Blood Vessels Blood capillaries Blood flow Brain Brain Edema Brain Injuries Cell Adhesion Molecules Cells Cessation of life Chemosensitization Chronic Cigarette Complement Data Deterioration Disease Dose Down-Regulation Environment Foundations Future Gelatinase A Genes Health Immune Immune response Impairment In Vitro Inflammation Inflammatory Inflammatory Response Ischemia Left Light Manuscripts Marketing Modeling NIH Program Announcements Nicotine Nitric Oxide Pathogenesis Pattern Physiology Play Property Proteins Public Health Publishing Rattus Reactive Oxygen Species Relative (related person)Research Risk Role Smoke Smoker Smoking Spin Trapping Sprague-Dawley Rats Stroke System Testing Tight Junctions Tobacco Tobacco Industry Tobacco smoke Tobacco smoking Toxic effect United States Up-Regulation acute coronary syndrome base capillary comparative cytokine desensitization hemodynamics in vivo macrophage monocyte non-smoker novel peripheral blood public health relevance research study response synergism tobacco exposure vascular endothelial dysfunction vector volunteer

项目摘要

DESCRIPTION (provided by applicant): Tobacco smoking is considered a major public health challenge, responsible for more than 400,000 deaths each year in the United States alone. To reduce the risk of health damage caused by tobacco smoke (TS) the tobacco industry is marketing and advertising a line of "reduced-exposure" tobacco products (such as "Advance" manufactured by Brown & Williamson Tobacco Corporation, "Omni" and Quest 3 manufactured by Vector Group Ltd), which claim to be less harmful than the leading "light" cigarette brands. However, the scientific evidence provided is insufficient to evaluate whether these products actually reduce the users' risk for tobacco-related diseases including those associated to vascular impairments. Despite the strong evidence for an association between tobacco smoke and vascular impairment, the impact of TS exposure on the blood-brain barrier (BBB) has been only marginally addressed and studies were limited to only few selective substances among the thousands contained in TS thus, leaving BBB research a substantial understudied area. To address these relevant health public concerns we propose a multimodal approach that involve the parallel use of 1) a novel humanized dynamic in vitro BBB model; 2) freshly isolated peripheral blood immune cells (PBMC) and platelets from smoker and non-smoker volunteers; 3) 3 vessel occlusion rat models of focal ischemia that will be used to complement the results in vitro and assess the likelihood and magnitude of secondary brain injury (brain edema) caused by TS exposure (from regular and "reduced-exposure") in synergism with temporary loss of blood flow. Based on these premises we propose to: 1. Evaluate the effect of tobacco smoke from reduced-exposure and regular tobacco products on BBB integrity and function and assess the immunoactivity of each tobacco product. 2. Investigate the effect of TS exposure on BBB function and viability in synergism with rheological changes and how this may impact the pathogenesis of secondary brain injury.

描述（由申请人提供）：吸烟被认为是一项重大的公共卫生挑战，仅在美国每年就造成超过 400,000 人死亡。为了降低烟草烟雾 (TS) 造成的健康损害风险，烟草业正在营销和宣传一系列“减少接触”烟草产品（例如 Brown & Williamson 烟草公司生产的“Advance”、“Omni”和 Quest）。 3 由 Vector Group Ltd 生产），声称比领先的“淡味”卷烟品牌危害更小。然而，所提供的科学证据不足以评估这些产品是否真正降低使用者患烟草相关疾病（包括与血管损伤相关的疾病）的风险。尽管有强有力的证据表明烟草烟雾与血管损伤之间存在关联，但 TS 暴露对血脑屏障 (BBB) 的影响只得到了轻微的解决，并且研究仅限于 TS 中所含的数千种物质中的少数选择性物质，因此，这使得 BBB 研究成为一个未被充分研究的领域。为了解决这些相关的健康公众问题，我们提出了一种多模式方法，其中包括并行使用 1) 新型人源化动态体外 BBB 模型； 2）从吸烟者和非吸烟者志愿者中新鲜分离的外周血免疫细胞（PBMC）和血小板； 3) 局灶性缺血的3个血管闭塞大鼠模型，将用于补充体外结果并评估协同作用下TS暴露（来自常规和“减少暴露”）引起的继发性脑损伤（脑水肿）的可能性和程度暂时性血流丧失。基于这些前提，我们建议： 1. 评估减少接触烟草产品和普通烟草产品产生的烟草烟雾对血脑屏障完整性和功能的影响，并评估每种烟草产品的免疫活性。 2. 研究 TS 暴露对 BBB 功能和活力与流变学变化的协同作用的影响，以及这如何影响继发性脑损伤的发病机制。