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

电子烟蒸气吸入会对肺细胞和生理功能产生不利影响，并改变全身炎症途径

• 批准号: 10220439
• 负责人: Laura Elise Crotty Alexander
• 金额: $ 36.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-28 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220439
• 关键词: Acute; Acute Lung Injury; Adult; Adverse effects; Advertisements; Affect; American; Bacteremia; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Pneumonia; Blood; Blood Circulation; Blood Pressure; Cardiovascular system; Cause of Death; Cells; Cessation of life; Chemicals; Child; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Cigarette; Cigarette Smoker; Communicable Diseases; Complex; Data; Development; Devices; Disease; Drug Delivery Systems; Electronic cigarette; Epithelial Cells; Event; Exposure to; Fibrosis; Future; Gene Expression; Heart Diseases; Heart Rate; Host Defense; Human; Impairment; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Interleukin-6; Intravenous; Kidney Failure; Lead; Link; Long-Term Effects; Lung; Lung diseases; Malignant Neoplasms; Minority; Modeling; Mus; Nasopharynx; Natural Immunity; Organ; Pathogenicity; Pathologic; Pathway interactions; Patients; Physiological; Plasma; Pneumonia; Population; Predisposition; Public Health; Pulmonary Emphysema; Race; Recommendation; Risk; Safety; Sales; Serum; Side; Skin Tissue; Smoke; Soft Tissue Infections; Staphylococcus aureus; System; Systemic disease; TNF gene; Temperature; Testing; Tight Junctions; Time; Tobacco; Tobacco smoke; Toxic effect; Up-Regulation; Virulence; Virulent; Woman; Work; aerosolized; airway hyperresponsiveness; antimicrobial; bronchial epithelium; carcinogenesis; cell type; cigarette smoke; coronary fibrosis; cytokine; cytokine release syndrome; defense response; e-cigarette aerosols; electronic cigarette use; electronic cigarette user; epidemiologic data; experimental study; gram-negative sepsis; human disease; human subject; immunoregulation; in vivo; infection risk; inflammatory marker; intraperitoneal; invention; kidney fibrosis; macrophage; methicillin resistant Staphylococcus aureus; mouse model; neutrophil; never smoker; nicotine use; nicotine vapor; non-smoker; pathogen; response; smoking cessation; systemic inflammatory response; theories; transcriptome sequencing; vaping; vapor; young adult

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.

摘要/摘要 慢性阻塞性肺病是第三大死因，且发病率持续上升。很多人都在尝试戒烟 使用电子烟吸烟，尽管数据表明电子烟的使用会产生不利影响 戒烟率。患者正在转向或增加电子烟的使用，因为广告称他们 完全安全。从不吸烟的年轻人（18-40 岁）正在吸电子烟 - 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、离体和体外数据表明 对宿主防御、肺部和全身炎症以及细菌毒力产生显着的不利影响。 电子烟可能会导致长期影响，例如慢性阻塞性肺病、心脏病和肾衰竭，但它 流行病学数据可以证明或反驳这一点还需要几十年的时间。 我们提出实验来评估电子烟蒸气对宿主原代人类气道细胞的影响 防御：巨噬细胞（正常人​​类受试者中>90%的气道细胞）和中性粒细胞（在 吸烟者的呼吸道 - 使用电子烟的最大人群）。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。与香烟的比较 烟雾对于回答最紧迫的问题之一很重要：电子烟比传统香烟更安全吗？ 香烟？我们将确定电子烟蒸汽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， 因为众所周知，炎症的增加和减少都会导致慢性疾病。我们将使用我们的 建立了电子烟蒸气吸入的小鼠模型，以便我们可以研究电子烟对人体的影响 人类常见疾病的背景，例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，抗生素耐药性细菌导致的侵袭性疾病和死亡的发生率正在上升 迅速。特别是，耐甲氧西林金黄色葡萄球菌 (MRSA) 是导致血液、 皮肤和软组织感染。 MRSA 长期定植于 20% 人口的鼻咽部。我们 最近发现，接触电子烟蒸汽后，MRSA 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 通过从电子烟使用者、吸烟者和吸烟者中分离菌株来研究体内金黄色葡萄球菌定殖的毒力 控制； 2. 评估电子烟对宿主防御和细菌毒力的生理影响 设置（感染 MRSA 的小鼠并同时吸入电子烟蒸气）以确定是否 电子烟对宿主防御和细菌致病性的有害影响以更复杂的方式发生 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共卫生产生重大影响，奠定了 为未来的研究以及向广大公众提出明智的电子烟建议奠定基础。