Inflammatory and Dysregulated Repair Responses to Inhaled Nicotine

对吸入尼古丁的炎症和失调修复反应

• 批准号: 9233280
• 负责人: IRFAN RAHMAN
• 金额: $ 46.68万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233280
• 关键词: 3-Dimensional; Acute; Adult; Advanced Glycosylation End Products; Aerosols; Affect; Air; Anti-Inflammatory Agents; Anti-inflammatory; Biological; Biological Markers; Breathing; C-reactive protein; Cell Aging; Cell Culture Techniques; Cell physiology; Cells; Chronic; Clinical; Data; Dinoprostone; Electronic Nicotine Delivery Systems; Electronic cigarette; Epithelial; Epithelial Cells; Epithelium; Exhalation; Exposure to; Extracellular Matrix; Fibrinogen; Fibroblasts; Generations; Glycerol; Health; Histology; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Knowledge; Liquid substance; Luciferases; Lung; Lung Inflammation; Lung diseases; Measures; Mesenchymal; Microscopy; Modeling; Monitor; Mus; Myofibroblast; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Outcome; Outcome Study; Oxidative Stress; PPAR gamma; Pathogenesis; Pathway interactions; Plasma; Pre-Clinical Model; Process; Property; Propylene Glycols; Prospective cohort study; Pulmonary Emphysema; Pulmonary function tests; Recruitment Activity; Reporter; Research; Respiratory physiology; Saliva; Smoking; Stress; System; Testing; Tissues; Tobacco; Toxic effect; Transforming Growth Factor beta; Urine; Vegetables; WNT Signaling Pathway; airway remodeling; alpha-bungarotoxin receptor; base; biological adaptation to stress; exosome; follow-up; healing; human subject; in vivo; in vivo Model; insight; lipid mediator; mechanical properties; morphometry; mouse model; receptor; repaired; response; second harmonic; senescence; transdifferentiation; vaping; vapor

SUMMARY Nicotine is a major component of nicotine delivery systems [Electronic Nicotine Delivery Systems (ENDS)] i.e. electronic cigarettes (e-cigs). Nicotine is known to have the addictive properties, and a knowledge gap exists on how inhaled nicotine affects the pulmonary system. Our supporting data show that ENDS nicotine aerosol delivery and exposure cause oxidative stress and inflammatory responses in human lung epithelial cells, fibroblasts, and in mouse lungs. Currently, no information is available on the biological effects of e-cig containing inhaled nicotine in humans and in mouse models. Inhaled nicotine may contribute to the pathogenesis of lung diseases in particular via lung inflammation, injurious, and dysregulated repair responses. We hypothesize that e-cig nicotine influences toxicity as evidenced by oxidative and inflammatory responses in humans and in mouse models, leading to dysregulated repair and emphysematous responses. Three specific aims are proposed to test this hypothesis: Aim 1: Inhaled nicotine induces lung and systemic inflammatory mediators in human subjects Determine the impact of inhaled nicotine in users and non-users of e-cigarettes. This will be accomplished by monitoring biomarkers of exposure (inflammatory, exosomes and lipid mediators by lipidomics) in human biofluids (saliva, Exhaled Breath Condensate, plasma, and urine) along with clinical outcomes (lung function tests) in a prospective cohort study (baseline and follow-up). Along with human studies, we plan to conduct mechanistic studies in vivo and in vitro. Aim 2: Inhaled nicotine induces lung inflammatory and dysregulated repair responses via its receptor Here, we will use a mouse preclinical model for mechanistic studies. We will determine if e-cigarettes containing low and high nicotine concentrations have differential pro-inflammatory and abnormal repair effects in vivo via the α7 nicotinic acetylcholine receptor (α7nAChR) dependent mechanism. Aim 3: Mechanisms whereby nicotine aerosol induces inflammatory and dysregulated cellular repair responses Determine inflammatory and dysregulated cellular repair responses to e-cigarette nicotine vapor in human lung epithelial cells and fibroblasts using the state-of-the-art reporter models (NF-κB luciferase) as well as a 3-D cell culture model. This will determine how nicotine affects cellular processes, such as early cellular senescence and myofibroblast differentiation, as well as lipogenic and myogenic pathways in healing/repair process. The outcomes of this study will provide an understanding of the clinical impact and mechanisms of inflammatory, senescence, and dysregulated repair responses following nicotine exposure in human subjects and, in primary lung cells in vitro and mouse model in vivo.

概括 尼古丁是尼古丁递送系统[电子尼古丁输送系统（末端）]的主要组成部分。 电子香烟（电子烟）。已知尼古丁具有添加特性，并且存在知识差距 关于遗传的尼古丁如何影响肺系统。我们的支持数据显示，结束尼古丁气雾剂 递送和暴露会导致人肺上皮细胞的氧化应激和炎症反应， 成纤维细胞和小鼠肺。当前，尚无有关电子烟的生物效应的信息 在人类和小鼠模型中包含遗传的尼古丁。吸入尼古丁可能有助于 肺部疾病的发病机理尤其是通过肺部感染，有害和修复失调 回答。我们假设E-cig尼古丁会影响毒性，如氧化和炎症性所证明的那样 人类和小鼠模型中的响应，导致修复和质膜反应失调。 提出了三个特定目标来检验这一假设： 目标1：吸入尼古丁会诱导人类受试者的肺和全身性炎症介质 确定继承尼古丁对电子烟的用户和非用户的影响。这将通过 在人类中监测暴露的生物标志物（炎症，外泌体和脂质介质） 生物流体（唾液，呼出的呼吸冷凝物，血浆和尿液）以及临床结果（肺功能 测试）在一项前瞻性队列研究（基线和随访）中。除人类研究外，我们计划进行 体内和体外的机械研究。 目标2：吸入尼古丁可通过其接收器引起肺部炎症和失调的修复反应 在这里，我们将使用小鼠临床前模型进行机械研究。我们将确定电子烟是否 含有低和高尼古丁浓度具有差异性促炎和异常修复效应 通过α7烟碱乙酰胆碱受体（α7NACHR）依赖机制进行体内。 AIM 3：尼古丁气溶胶诱导炎症和失调的细胞修复机制 回答 确定人肺中对电子烟尼古丁蒸气的炎症和失调的细胞修复反应 使用最先进的报告基因模型（NF-κB荧光素酶）以及3-D细胞的上皮细胞和成纤维细胞 文化模型。这将决定尼古丁如何影响细胞过程，例如早期的细胞感应 以及肌成纤维细胞的分化，以及愈合/修复过程中的脂肪生成和肌源性途径。 这项研究的结果将提供对临床影响和机制的理解 人类受试者尼古丁暴露后的炎症，感应和失调的修复反应 并且，在体外的体外和小鼠模型中。