Electronic Cigarette Vapor Inhalation Adversely Affects Lung Cellular and Physiologic Function and Alters Systemic Inflammatory Pathways

总结/摘要 COPD是第三大死亡原因，发病率持续上升。很多人都想戒烟 使用电子烟吸烟，尽管数据显示电子烟的使用会对健康产生不利影响。 戒烟率。患者正在转向或增加电子烟的使用，因为广告说他们是 绝对安全年轻的成年人（18-40）从不吸烟的人正在吸电子烟-吸入含有 尼古丁和其他化学物质。我们的体内、体外和离体数据表明， 对宿主防御、肺部和全身炎症以及细菌毒力的显著不利影响。 Vaping可能会导致长期影响，如COPD，心脏病和肾衰竭的发展，但它 流行病学数据将需要几十年才能证明或反驳它。 我们提出实验来评估电子烟蒸汽对宿主的原代人气道细胞的影响 防御：巨噬细胞（正常人受试者中>90%的气道细胞）和中性粒细胞（在正常人受试者中升高）。 吸烟者的气道-使用电子烟的最大人口）。这些细胞直接暴露于 呼吸道中吸入的蒸气，是肺部和血液中宿主防御的支柱。与香烟相比 吸烟对于回答一个最紧迫的问题很重要：电子烟比传统香烟更安全吗？ 香烟吗我们将确定电子烟蒸汽是否会对巨噬细胞的能力产生负面影响， 中性粒细胞杀死常见病原体，并检查电子烟是否失调炎症反应， 因为已知炎症的增加和减少都会引起慢性疾病。我们将用我们 建立了电子烟蒸气吸入小鼠模型，以便我们研究电子烟在 常见的人类疾病，如革兰氏阴性脓毒症，急性肺损伤和革兰氏阳性 肺炎和菌血症。 最后，由于抗生素耐药细菌引起的侵袭性疾病和死亡的发生率正在增长 迅速特别地，耐甲氧西林金黄色葡萄球菌（MRSA）是血流的主要原因， 皮肤和软组织感染。MRSA在20%的人群的鼻咽部长期定植。我们 最近发现，MRSA在暴露于电子烟蒸汽后更难杀死，毒性更强， 传统的烟草烟雾。在本提案中，我们将：1。确定电子烟蒸汽是否促进 定殖S.通过从电子烟使用者、吸烟者和 控制;和2.评估电子烟对生理环境中宿主防御和细菌毒力的影响 设置（MRSA定殖小鼠并同时吸入电子烟蒸汽），以确定是否 电子烟对宿主防御和细菌致病性的有害影响发生在一个更复杂的 设置，就像在人类气道中发生的那样。这些研究可能会对公共卫生产生重大影响， 为未来的研究奠定基础，并向公众提出明智的电子烟建议。

SUMMARY/ABSTRACT COPD is the 3rd leading cause of death and incidence continues to rise. Many people are trying to quit smoking by using electronic (e)-cigarettes, even though data suggest that e-cigarette use adversely impacts cessation rates. Patients are switching to or adding on e-cigarette use because advertisements say they are completely safe. Young adult (18-40) never smokers are vaping e-cigarettes - inhaling vapor containing nicotine and other chemicals from these drug delivery devices. Our in vivo, ex vivo and in vitro data suggest significant adverse effects on host defenses, inflammation in the lung and systemically, and bacterial virulence. Vaping may lead to long-term effects, such as development of COPD, heart disease, and kidney failure, but it will be decades before epidemiologic data can demonstrate or disprove it. We propose experiments to evaluate effects of e-cigarette vapor on primary human airway cells of host defense: macrophages (>90% of airway cells in normal human subjects) and neutrophils (elevated in the airways of cigarette smokers - the largest population using e-cigarettes). These cells are directly exposed to inhaled vapor in the airways and are the mainstays of host defense in lung and blood. Comparison to cigarette smoke is important to answer one of the most urgent questions: Are e-cigarettes safer than conventional cigarettes? We will determine whether e-cigarette vapor negatively impacts the ability of macrophages and neutrophils to kill common pathogens and examine whether e-cigarettes dysregulate inflammatory responses, as both increases and decreases in inflammation are known to cause chronic disease. We will use our established mouse model of e-cigarette vapor inhalation, such that we may study effects of e-cigarettes in the setting of common human diseases, such as gram-negative sepsis, acute lung injury, and gram-positive pneumonia and bacteremia. Finally, the incidence of invasive disease and death due to antibiotic resistant bacteria is growing rapidly. In particular, methicillin resistant Staphylococcus aureus (MRSA) is the leading cause of bloodstream, skin and soft tissue infections. MRSA colonizes the nasopharynx of 20% of the population chronically. We recently found that MRSA is harder to kill and more virulent after exposure to e-cigarette vapor as well as conventional tobacco smoke. In this proposal we will: 1. Determine whether e-cigarette vapor promotes virulence in colonizing S. aureus in vivo by isolating strains from e-cigarette users, cigarette smokers and controls; and 2. Evaluate e-cigarette effects on both host defense and bacterial virulence in a physiologic setting (mice colonized with MRSA and concomitantly inhaling e-cigarette vapor) to determine whether deleterious effects of e-cigarettes on host defenses and bacterial pathogenicity occur in a more complex setting, as would happen in human airways. These studies may have a major public health impact, laying groundwork for future studies and for making informed e-cigarette recommendations to the public at large.