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

摘要/摘要 慢性阻塞性肺病是导致死亡的第三大原因，而且发病率还在继续上升。很多人都想戒烟 使用电子烟吸烟，即使数据表明电子烟的使用会产生不利影响 戒毒率。患者正在改用或增加电子烟的使用，因为广告说他们 完全安全。年轻人(18-40岁)从不吸烟者正在蒸发电子烟-吸入含有 这些药物输送装置中的尼古丁和其他化学物质。我们的体内、体外和体外数据表明 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。 蒸发可能会导致长期影响，如慢性阻塞性肺病、心脏病和肾衰竭，但它 流行病学数据将在几十年后才能证明或反驳这一点。 我们建议通过实验来评估电子烟蒸气对宿主原代人体呼吸道细胞的影响。 防御：巨噬细胞(正常人90%的呼吸道细胞)和中性粒细胞(在正常人群中升高 吸烟者的航空公司--使用电子烟的最大人口)。这些细胞直接暴露在 吸入的蒸气在呼吸道和肺部和血液中是宿主防御的中流砥柱。与香烟相比 烟对于回答一个最紧迫的问题很重要：电子烟比传统烟更安全吗？ 要香烟吗？我们将确定电子烟蒸气是否会对巨噬细胞和 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， 因为炎症的增加和减少都会导致慢性病。我们将使用我们的 建立了电子烟烟雾吸入的小鼠模型，以便我们可以研究电子烟对小鼠的影响 人类常见疾病的背景，如革兰氏阴性败血症、急性肺损伤和革兰氏阳性 肺炎和菌血症。 最后，由抗药性细菌引起的侵袭性疾病和死亡的发生率正在上升。 迅速地。特别是，耐甲氧西林金黄色葡萄球菌(MRSA)是导致血流的主要原因， 皮肤和软组织感染。耐甲氧西林金黄色葡萄球菌慢性定植于20%的人口的鼻咽。我们 最近发现，接触电子烟蒸气后，MRSA更难杀死，毒力更强 传统的烟草烟雾。在这项提案中，我们将：1.确定电子烟蒸气是否促进 从电子烟使用者、吸烟者和吸烟者分离的金黄色葡萄球菌在体内定植的毒力 2.从生理角度评估电子烟对宿主防御和细菌毒力的影响 设置(感染MRSA并同时吸入电子烟蒸气的小鼠)以确定 电子烟对宿主防御和细菌致病性的有害影响发生在更复杂的 环境，就像在人类呼吸道中发生的那样。这些研究可能会对公众健康产生重大影响， 为未来的研究和向广大公众提出知情的电子烟建议奠定基础。

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.