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）：烟草烟雾对健康有破坏性影响。尽管有证据表明烟草对肺部和其他器官有害，但仍有大约20%的美国人经常吸烟。吸烟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，慢性阻塞性肺病是肺癌常见且重要的独立危险因素，因此，慢性阻塞性肺病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，这表明肺部的先天防御系统已经受损。这些变化被认为与COPD的发病机制有关。为了应对旨在限制香烟销售的新立法，烟草业开发了旨在逃避这一立法的烟草替代品。“小雪茄”的使用通常是加了香味的，因此