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

基本信息

批准号：
8582362
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
项目类别：
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/8582362
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

项目摘要

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）：烟草烟雾对健康有毁灭性的影响。尽管有证据表明烟草会伤害肺部和其他器官，但> 20％的美国人口仍在定期抽烟。烟草烟雾会导致COPD和肺癌。长期的烟草暴露会触发肺部的炎症反应，从而有助于COPD的发病机理。此外，COPD是肺癌的常见且重要的独立危险因素，因此，COPD可能被认为是癌前状态。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，这表明肺的先天防御系统受到了损害。这些变化被认为有助于COPD的发病机理。为了应对旨在遏制卷烟的新立法的回应，烟草业开发了试图逃避这项立法的烟草替代品。使用“小雪茄”的使用通常是调味的，因此对年轻吸烟者有吸引力的人已经上升了240％，而在北卡罗来纳州，多达50％的大学生声称尝试过水烟，> 10％是普通的水烟吸烟者。尽管这些烟草替代品中的许多替代品被认为是“更安全的”，但它们对肺部健康的影响尚不清楚。因此，我们建议衡量烟草替代品对肺部天生防御系统的潜在不利影响。 I和II项目（Tarran和Kesimer）致力于确定烟草替代品对该系统特定方面的影响，即Airway Surfie Surface液体稳态和粘蛋白/粘液，并将使用创新的体外烟雾曝光系统来测量天生肺防御的特定生物标志物以及从烟道space Airway samples samples frombace samples ofbacco sokebacco ofbacco osbacco osbacco ofbacco osbacco osbacco。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，更亲密地模仿人类患有COPD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，并确定体内暴露于替代烟草后的表观遗传变化。项目IV（JASPERS）将确定与从人类志愿者获得的样品中与烟草替代品相关的基因组生物标志物。专注于这些受试者中抗病毒宿主防御的变化，该模型将用于将其他项目中的观察结果与感染了感染活流感病毒的人类获得的发现。因此，使用人体和小鼠在体内和体外模型中，该项目将确定与烟草诱导的肺部防御变化相关的新型生物标志物，可以将其应用于了解任何新的和新兴的烟草产品的潜在毒性。相关性：烟草暴露会损害肺部天生防御系统的多个臂，包括粘液清除（即肺部清洁自身的能力）和对吸入病原体（例如病毒）的耐药性。这些变化是COPD发展的原因。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来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）吸烟者那里获得生物标志物样品。这种知识可能有助于消除新的烟草产品代表香烟更安全的替代品的神话。