The Impact of Tobacco Exposure on the Lungs Innate Defense System

烟草暴露对肺部先天防御系统的影响

• 批准号: 8737945
• 负责人: ROBERT TARRAN
• 金额: $ 400万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737945
• 关键词: Acute; Adenosine; Affect; Algorithms; Animal Model; Antiviral Agents; Attenuated; Biological Markers; Biological Models; Breathing; Cancerous; Cathepsins B; Cells; Cellular biology; Chemicals; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cigar; Cigarette; Complex; Coughing; Coupled; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Dehydration; Development; Environment; Epigenetic Process; Epithelial; Epithelium; Equilibrium; Event; Exposure to; Failure; Flavoring; Genetic; Genomics; Health; Homeostasis; Host Defense; Human; Human Volunteers; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Life; Lung; Lung Inflammation; Lung diseases; Malignant neoplasm of lung; Measurement; Measures; Metaplasia; Modeling; Mucins; Mucous body substance; Mus; Neoplasm Metastasis; Nucleotides; Obstructive Lung Diseases; Organ; Pathogenesis; Pathway interactions; Pb clearance; Phenotype; Population; Process; Proteins; Purine Nucleotides; Purines; Resistance; Respiratory System; Respiratory tract structure; Risk Factors; Sales; Sampling; Signal Transduction; Smoke; Smoker; Sodium Chloride; Staging; Statutes and Laws; System; Testing; Time; Tobacco; Tobacco Industry; Tobacco smoke; Toxic effect; Toxin; Virus; Virus Diseases; Water; airway surface liquid; arm; extracellular; hookah; in vitro Model; in vivo; in vivo Model; inflammatory marker; influenzavirus; innovation; novel; pathogen; purine; respiratory toxin; response; sensor; tobacco exposure; university student

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.

描述（由申请人提供）：烟草烟雾对健康具有破坏性影响。尽管有证据表明烟草会损害肺部和其他器官，但超过 20% 的美国人仍然经常吸烟。烟草烟雾会导致慢性阻塞性肺病和肺癌。长期接触烟草会引发肺部炎症反应，从而导致慢性阻塞性肺病的发病机制。此外，COPD是肺癌的常见且重要的独立危险因素，因此，COPD可被认为是癌前状态。更具体地说，烟草烟雾会导致气道表面液体/粘液脱水并增加病毒感染的发生率，这表明肺部的先天防御系统已受损。这些变化被认为有助于 COPD 的发病机制。为了响应旨在限制卷烟销售的新立法，烟草业开发了试图规避该立法的烟草替代品。使用经常调味的“小雪茄”，因此 对年轻吸烟者的吸引力上升了 240%，而在北卡罗来纳州，高达 50% 的大学生声称尝试过水烟，其中超过 10% 的人是经常吸水烟的人。虽然许多这些烟草替代品被认为“更安全”，但它们对肺部健康的影响尚不清楚。因此，我们建议衡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肺防御的特定生物标志物，并从替代烟草吸烟者那里获取气道样本。在项目 III (Doerschuk) 中，我们建议开发一种新型的烟雾暴露动物模型，该模型更接近地模拟慢性阻塞性肺病患者的慢性支气管炎表型。该模型将用于验证项目 I 和 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。该模型着眼于这些受试者抗病毒宿主防御的变化，将用于将其他项目中的观察结果与从感染活减毒流感病毒的人类中获得的发现相结合。因此，利用人和小鼠的体内和体外模型，该项目将鉴定与烟草引起的肺部先天防御变化相关的新型生物标志物，这些生物标志物可用于了解任何新型和新兴烟草产品的潜在毒性。 相关性：接触烟草会损害肺部先天防御系统的多个部分，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 COPD 的发展。新兴烟草产品对肺部先天防御系统的潜在影响尚不清楚。我们建议使用体外和体内模型系统来描述此类烟草替代品对肺部健康的影响，并从水烟和小雪茄等烟草替代品的吸烟者那里获取生物标志物样本。这些知识可能有助于消除新烟草产品代表卷烟更安全替代品的神话。