Testing tobacco smoke toxicity at the blood-brain barrier

通过血脑屏障测试烟草烟雾毒性

• 批准号: 8039874
• 负责人: Luca Cucullo
• 金额: $ 8.15万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039874
• 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; research study; response; synergism; tobacco exposure; vascular endothelial dysfunction; vector; volunteer

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. PUBLIC HEALTH RELEVANCE: Active and passive tobacco smoking are associated with dysfunction of vascular endothelial physiology in a causative and dose dependent way. 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 critical issues, we propose to evaluate the effect of tobacco smoke from reduced-exposure and regular tobacco products on BBB integrity and function. We also propose to 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. This proposal is in response to the PA-09-046. This program announcement specifically asks to explore the differential toxicity of various tobacco and nicotine products. In this respect, we believe that our study will produce a remarkable impact on the awareness of tobacco smoke toxicity in an under considered health area and will provide the foundations for additional studies.

描述（由申请人提供）：烟草吸烟被认为是一项重大的公共卫生挑战，仅在美国，每年造成40万多人死亡。为了降低烟草烟雾（TS）造成健康损害的风险，烟草行业是营销和广告“减少暴露”烟草产品（例如Brown＆Williamson烟草公司制造的“ Advance”烟草产品，“ Omni”和Quest 3由Vector Group Ltd制造），声称危害不如领先的“轻”卷烟品牌。但是，所提供的科学证据不足以评估这些产品是否真的降低了用户患烟草相关疾病的风险，包括与血管障碍相关的疾病。尽管有强有力的证据表明烟草烟与血管障碍之间存在关联，但TS暴露对血脑屏障（BBB）的影响仅略有解决，并且研究仅限于TS中数千种选择性物质，因此仅限于TS中的数千种选择性物质。离开BBB研究是一个大量研究的领域。为了解决这些相关的健康公众关注，我们提出了一种多模式的方法，涉及并行使用1）一种新型的人性化动态体外BBB模型； 2）新鲜分离的外周血免疫细胞（PBMC）和来自吸烟者和非吸烟志愿者的血小板； 3）3局部缺血的血管阻塞大鼠模型，将用于在体外补充结果并评估由TS暴露引起的继发性脑损伤的可能性和大小随着血流的暂时损失。基于这些前提，我们建议：1。评估烟草烟雾降低和常规烟草产物对BBB完整性和功能的影响，并评估每种烟草产物的免疫活性。 2。研究TS暴露对与流变学变化的协同作用中BBB功能的影响以及这可能如何影响继发性脑损伤的发病机理。 公共卫生相关性：积极和被动的烟草吸烟与血管内皮生理的功能障碍有关，依赖性和剂量依赖性方式。尽管有强有力的证据表明烟草烟与血管障碍之间存在关联，但TS暴露对血脑屏障（BBB）的影响仅略有解决，并且研究仅限于TS中数千种选择性物质，因此仅限于TS中的数千种选择性物质。离开BBB研究是一个大量研究的领域。为了解决这些关键问题，我们建议评估烟草烟雾减少的暴露和常规烟草产品对BBB完整性和功能的影响。我们还建议研究TS暴露对BBB功能的影响和与流变学变化的协同作用，以及这可能如何影响继发性脑损伤的发病机理。该建议是对PA-09-046的回应。该计划公告特别要求探索各种烟草和尼古丁产品的差异毒性。在这方面，我们认为我们的研究将对未经考虑的健康领域中烟草烟毒性的意识产生显着影响，并将为其他研究提供基础。