The Impact of Tobacco Exposure on the Lungs Innate Defense System

描述(申请人提供)：烟草烟雾对健康有毁灭性的影响。尽管有证据表明烟草会损害肺部和其他器官，但仍有20%的美国人继续定期吸烟。烟草烟雾会导致慢性阻塞性肺病和肺癌。长期接触烟草会在肺部触发炎症反应，从而导致COPD的发病。此外，COPD是肺癌常见且重要的独立危险因素，因此，COPD可被认为是一种癌前状态。更具体地说，烟草烟雾会导致呼吸道表面液体/粘液脱水，并增加病毒感染的发生率，这表明肺的天然防御系统受到了损害。这些变化被认为与COPD的发病机制有关。作为对旨在限制香烟销售的新立法的回应，烟草行业开发了烟草替代品，试图逃避这项立法。“小雪茄”的使用，通常是加了味的，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%的人是水烟的常客。虽然这些烟草替代品中的许多被认为是“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固有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这一系统的特定方面的影响，即呼吸道表面液体动态平衡和粘蛋白/粘液，并将使用一种创新的体外烟雾暴露系统来测量先天肺防御的特定生物标记物，以及从替代烟草吸烟者身上获取呼吸道样本。在项目III(Doerschuk)中，我们建议开发一种新的烟雾暴露动物模型，更接近于COPD患者的慢性支气管炎表型。该模型将用于验证项目I和项目II中看到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学变化。项目四(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记物。着眼于这些受试者在抗病毒宿主防御方面的变化，该模型将被用于将其他项目中的观察结果与从感染减毒活流感病毒的人类中获得的结果相结合。因此，利用人体和小鼠的体内和体外模型，该项目将识别与烟草诱导的肺固有防御变化相关的新的生物标记物，这些生物标记物可以用于了解任何新出现的烟草产品的潜在毒性。 相关性：烟草暴露会损害肺部固有防御系统的多个手臂，包括粘液清除(即肺部自我清洁的能力)和对病毒等吸入病原体的抵抗力。这些变化有助于慢性阻塞性肺疾病的发展。新出现的烟草产品对肺部固有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来描述这种烟草替代品对肺部健康的影响，以及从吸烟者那里获得诸如水烟和小雪茄等烟草替代品的生物标志物样本。这些知识可能有助于消除认为新的烟草产品是香烟的更安全替代品的神话。

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.