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: 10089469
• 负责人: IRFAN RAHMAN
• 金额: $ 43.3万
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089469
• 关键词: 3-Dimensional; Acute; Adult; Advanced Glycosylation End Products; Aerosols; Affect; Agonist; Air; Anti-Inflammatory Agents; Biological; Biological Markers; C-reactive protein; Cell Aging; Cell Culture Techniques; Cell physiology; Cells; Chronic; Clinical; Data; Dinoprostone; Electronic Nicotine Delivery Systems; Electronic cigarette; Epithelial; Epithelial Cells; Exhalation; Extracellular Matrix; Fibrinogen; Fibroblasts; Generations; Health; Histology; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inhalation; Interleukin-1; Interleukin-6; Knowledge; Liquid substance; Luciferases; Lung; Lung Inflammation; Lung diseases; Measures; Mesenchymal; Microscopy; Modeling; Monitor; Mus; Myofibroblast; Nicotine; 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; Reporter; Research; Saliva; Smoking; Stress; System; Testing; Tissues; Toxic effect; Transforming Growth Factor beta; Urine; WNT Signaling Pathway; airway remodeling; alpha-bungarotoxin receptor; base; biological adaptation to stress; e-cigarette aerosols; electronic cigarette user; exosome; exposed human population; follow-up; healing; human model; human subject; in vivo; in vivo Model; insight; lipid mediator; lipidomics; lung injury; mechanical properties; morphometry; mouse model; nicotine exposure; nicotine inhalation; nicotine vapor; pulmonary function; receptor; recruit; repaired; response; second harmonic; senescence; tobacco products; transdifferentiation; vaping; vapor; vegetable glycerin

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 尼古丁是尼古丁输送系统[电子尼古丁输送系统（ENDS）]的主要组成部分，即 电子烟（e-cigs）。众所周知，尼古丁具有成瘾性，但存在知识差距 关于吸入尼古丁如何影响肺部系统。我们的支持数据表明 ENDS 尼古丁气雾剂 递送和暴露会引起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部。目前，尚无关于电子烟生物效应的信息 在人类和小鼠模型中含有吸入尼古丁。吸入尼古丁可能会导致 肺部疾病的发病机制，特别是通过肺部炎症、损伤和失调的修复 回应。我们假设电子烟尼古丁会影响毒性，这一点可以通过氧化和炎症来证明 人类和小鼠模型中的反应，导致修复失调和肺气肿反应。 提出了三个具体目标来检验这一假设： 目标 1：吸入尼古丁诱导人体产生肺部和全身炎症介质 确定吸入尼古丁对电子烟使用者和非使用者的影响。这将通过以下方式完成 监测人体暴露的生物标志物（通过脂质组学检测炎症、外泌体和脂质介质） 生物液体（唾液、呼出气冷凝液、血浆和尿液）以及临床结果（肺功能） 测试）在前瞻性队列研究（基线和随访）中。除了人类研究之外，我们还计划进行 体内和体外机制研究。 目标 2：吸入尼古丁通过其受体诱导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制研究。我们将确定电子烟是否 含有低浓度和高浓度的尼古丁具有不同的促炎和异常修复作用 在体内通过α7烟碱乙酰胆碱受体（α7nAChR）依赖性机制。 目标 3：尼古丁气雾剂诱导炎症和失调细胞修复的机制 回应 确定人肺中电子烟尼古丁蒸气的炎症和失调细胞修复反应 使用最先进的报告模型（NF-κB 荧光素酶）以及 3-D 细胞分析上皮细胞和成纤维细胞 文化模型。这将确定尼古丁如何影响细胞过程，例如早期细胞衰老 和肌成纤维细胞分化，以及愈合/修复过程中的脂肪生成和肌生成途径。 这项研究的结果将有助于了解临床影响和机制 人类受试者暴露于尼古丁后的炎症、衰老和失调的修复反应 并且，在体外原代肺细胞和体内小鼠模型中。

项目成果

Differential plasma exosomal long non-coding RNAs expression profiles and their emerging role in E-cigarette users, cigarette, waterpipe, and dual smokers.

• DOI: 10.1371/journal.pone.0243065
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kaur G;Singh K;Maremanda KP;Li D;Chand HS;Rahman I
• 通讯作者: Rahman I

Inflammatory biomarkers and growth factors in saliva and gingival crevicular fluid of e-cigarette users, cigarette smokers, and dual smokers: A pilot study.

电子烟使用者、吸烟者和双重吸烟者唾液和龈沟液中的炎症生物标志物和生长因子：一项试点研究。

• DOI: 10.1002/jper.19-0457
• 发表时间: 2020-10
• 期刊: JOURNAL OF PERIODONTOLOGY
• 影响因子: 4.3
• 作者: Ye, Dongxia;Gajendra, Sangeeta;Lawyer, Gina;Jadeja, Neelam;Pishey, Deepa;Pathagunti, Srinivasa;Lyons, Janet;Veazie, Peter;Watson, Gene;McIntosh, Scott;Rahman, Irfan
• 通讯作者: Rahman, Irfan

Circadian clock-based therapeutics in chronic pulmonary diseases.

• DOI: 10.1016/j.tips.2022.09.004
• 发表时间: 2022-12
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Giri A;Rahman I;Sundar IK
• 通讯作者: Sundar IK

Role of inner mitochondrial protein OPA1 in mitochondrial dysfunction by tobacco smoking and in the pathogenesis of COPD.

• DOI: 10.1016/j.redox.2021.102055
• 发表时间: 2021-09
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Maremanda KP;Sundar IK;Rahman I
• 通讯作者: Rahman I

Circadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization.

• DOI: 10.1038/s41467-023-36896-0
• 发表时间: 2023-03-09
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Wang, Qixin;Sundar, Isaac Kirubakaran;Lucas, Joseph H.;Park, Jun-Gyu;Nogales, Aitor;Martinez-Sobrido, Luis;Rahman, Irfan
• 通讯作者: Rahman, Irfan