The Impact of Tobacco Exposure on the Lungs Innate Defense System

描述（由申请人提供）：烟草烟雾对健康有破坏性影响。尽管有证据表明烟草会损害肺部和其他器官，但仍有超过20%的美国人继续定期吸烟。吸烟会导致慢性阻塞性肺病和肺癌。长期烟草暴露引发肺部炎症反应，导致COPD发病。此外，COPD是肺癌的常见且重要的独立风险因素，因此，COPD可被认为是癌前状态。更具体地说，烟草烟雾导致气道表面液体/粘液脱水和病毒感染的发病率增加，表明肺的先天防御系统已经受损。这些变化被认为有助于COPD的发病机制。为了应对旨在限制香烟销售的新立法，烟草业开发了烟草替代品，试图规避这一立法。使用“小雪茄”，这往往是调味，因此， 在北卡罗来纳州，高达50%的大学生声称尝试过水烟，其中>10%是经常抽水烟的人。虽然这些烟草替代品中有许多被认为是“更安全”的，但它们对肺部健康的影响尚不清楚。因此，我们建议测量烟草替代品对肺部先天防御系统的潜在不利影响。项目I和II（Tarran和Kesimer）的重点是确定烟草替代品对该系统特定方面的影响，即气道表面液体稳态和粘蛋白/粘液，并将使用创新的体外烟雾暴露系统来测量先天性肺防御的特定生物标志物，以及从替代烟草吸烟者那里获得气道样本。在项目III（Doerschuk）中，我们建议开发一种新的烟雾暴露动物模型，更接近地模拟慢性支气管炎患者中观察到的慢性支气管炎表型。该模型将用于验证项目I和II中的烟草暴露生物标志物，以及确定体内暴露于替代烟草后的表观遗传变化。项目IV（Jaspers）将从人类志愿者获得的样本中确定与烟草替代品相关的基因组生物标志物。关注这些受试者中抗病毒宿主防御的变化，该模型将用于整合其他项目中的观察结果与从感染减毒活流感病毒的人中获得的发现。因此，使用人类和小鼠体内和体外模型，该项目将确定与烟草诱导的肺先天防御变化相关的新生物标志物，这些生物标志物可用于了解任何新的和新兴的烟草产品的潜在毒性。 相关性：烟草暴露损害肺先天防御系统的多个分支，包括粘液清除（即，肺自身清洁的能力）和抵抗吸入的病原体如病毒。这些变化有助于COPD的发展。新的和新兴的烟草产品对肺部先天防御系统的潜在影响是完全未知的。我们建议使用体外和体内模型系统描述这种烟草替代品对肺部健康的影响，并从烟草替代品（如水烟和小雪茄）的吸烟者中获得生物标志物样本。这些知识可能有助于消除新烟草产品是香烟更安全的替代品的神话。

DESCRIPTION (provided by applicant): Tobacco smoke has a devastating impact on health. Despite evidence that tobacco harms lungs and other organs, >20% of the U.S. population continue to smoke regularly. Tobacco smoke causes COPD and lung cancer. Long term tobacco exposure triggers an inflammatory response in the lung that contributes to the pathogenesis of COPD. Moreover, COPD is a common and important independent risk factor for lung cancer and thus, COPD may be thought of as a pre-cancerous state. More specifically, tobacco smoke causes airway surface liquid/mucus dehydration and increased incidence of viral infections, suggesting that the Lung's Innate Defense System has been impaired. These changes are thought to contribute to the pathogenesis of COPD. In response to new legislation aimed at curbing the sale of cigarettes, the tobacco industry has developed tobacco alternatives that seek to evade this legislation. Usage of "little cigars" which are often flavored and are thus attractive to younger smokers, has risen 240%, while in NC, up to 50% of college students claim to have tried Hookah, with >10% being regular Hookah smokers. Whilst many of these tobacco alternatives are perceived to be "safer", their impact on lung health is unknown. Thus, we propose to measure the potential adverse impact of tobacco alternatives on the lung's innate defense system. Projects I and II (Tarran and Kesimer) are focused on determining the impact of tobacco alternatives on specific aspects of this system, namely, airway surface liquid homeostasis and mucin/mucus and will use an innovative in vitro smoke exposure system to measure specific biomarkers of innate lung defense as well as obtain airway samples from smokers of alternate tobacco. In Project III (Doerschuk), we propose to develop a novel animal model of smoke exposure that more closely mimics the chronic bronchitis phenotype seen in humans with COPD. This model will be used to validate tobacco exposure biomarkers seen in Projects I and II as well as to determine epigenetic changes following in vivo exposure to alternative tobacco. Project IV (Jaspers) will determine genomic biomarkers associated with tobacco alternatives from samples obtained from human volunteers. Focusing on changes in antiviral host defense in these subjects, this model will be used to integrate observations made in the other projects with findings obtained from humans infected with live attenuated influenza virus. Thus, using human and mouse in vivo and in vitro models, this project will identify novel biomarkers associated with tobacco-induced changes in lung innate defense, which can be applied to understand potential toxicity of any new and emerging tobacco products. RELEVANCE: Tobacco exposure impairs multiple arms of the lung's innate defense system including mucus clearance (i.e., the lung's ability to clean itself) and resistance to inhaled pathogens such as viruses. These changes are contributory to the development of COPD. The potential impact of new and emerging tobacco products on the lung's innate defense system is totally unknown. We propose to describe the effects of such tobacco alternatives on lung health using in vitro and in vivo model systems as well as obtaining biomarker samples from smokers of tobacco alternatives such as Hookah and Little Cigars. Such knowledge may help dispel the myth that new tobacco products represent a safer alternative to cigarettes.