Testing tobacco smoke toxicity at the blood-brain barrier

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40多万人死亡。为了减少烟草烟雾对健康造成损害的风险，烟草业正在推销和宣传一系列“减少接触”的烟草产品（如布朗和威廉姆森烟草公司生产的“前进”，矢量集团有限公司生产的“全方位”和Quest 3），这些产品声称比领先的“轻”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确实降低了使用者患烟草相关疾病的风险，包括与血管损伤有关的疾病。尽管有强有力的证据表明烟草烟雾和血管损伤之间存在关联，但TS暴露对血脑屏障（BBB）的影响仅得到了少量的解决，研究仅限于TS中所含的数千种物质中的少数几种，因此，BBB研究是一个大量研究不足的领域。为了解决这些相关的健康问题，我们提出了一种多模式方法，其涉及平行使用1）新型人源化动态体外BBB模型; 2）来自吸烟者和非吸烟者志愿者的新鲜分离的外周血免疫细胞（PBMC）和血小板;第三章3种血管闭塞大鼠局灶性缺血模型，将用于补充体外结果，并评估继发性缺血的可能性和程度。TS暴露（来自常规和“减少暴露”）与暂时性血流损失协同作用引起的脑损伤（脑水肿）。基于这些前提，我们建议：1。评估来自减少暴露和常规烟草产品的烟草烟雾对BBB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暴露与流变学变化协同作用对BBB功能和活力的影响，以及这可能如何影响继发性脑损伤的发病机制。 公共卫生相关性：主动吸烟和被动吸烟与血管内皮生理功能障碍相关，且呈剂量依赖性。尽管有强有力的证据表明烟草烟雾和血管损伤之间存在关联，但TS暴露对血脑屏障（BBB）的影响仅得到了少量的解决，研究仅限于TS中所含的数千种物质中的少数几种，因此，BBB研究是一个大量研究不足的领域。为了解决这些关键问题，我们建议评估烟草烟雾对BBB完整性和功能的影响。我们还建议研究TS暴露对BBB功能和活力的影响，以及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制。本提案是对PA-09-046的回应。该计划特别要求探索各种烟草和尼古丁产品的不同毒性。在这方面，我们相信，我们的研究将产生显着的影响，烟草烟雾毒性的认识在一个考虑不足的健康领域，并将提供进一步的研究基础。

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.