Inflammatory and Dysregulated Repair Responses to Inhaled Nicotine

对吸入尼古丁的炎症和失调修复反应

基本信息

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
项目类别：
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

项目摘要

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的主要组成部分众所周知，尼古丁具有上瘾的特性，并且存在一个知识差距关于吸入尼古丁的吸入如何影响我们的肺部系统。递送和暴露会导致人肺上皮细胞的氧化应激和炎症反应，纤维细胞和小鼠肺部。在人类和小鼠模型中包含。肺部疾病的发病机理尤其是通过肺肺炎症和失调的修复我们的回应。人类和小鼠模型中的响应，导致不合格的修复和杂质反应。支撑了三个具体目标以检验这一假设： AIM 1：吸入尼古丁诱导肺肺和全身性炎症介质在人类受试者中确定吸入尼古丁在电子烟的用户和非用户的影响。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（肺功能）测试）在一项前瞻性队列研究中（基线和随访）。体内和体外的机械研究。目标2：吸入尼古丁可通过其受体诱导肺炎症和功能障碍响应反应在这里，我们将使用鼠标现有的模型进行机械研究。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：尼古丁气溶胶会诱导炎症和失调的细胞修复机制回答确定人肺中电子烟尼古丁蒸气的炎症和失调的细胞修复使用泰特记者（NF-κB荧光素酶）以及3-D细胞的上皮细胞和成纤维细胞培养模型。这将决定尼古丁如何影响细胞过程和肌细胞的区分，以及愈合/修复过程中的脂肪生成和肌源性途径。临床影响的临床影响和机制的结果。人类受试者尼古丁暴露后炎症，衰老和失调的修复呼吸并且，在体外的体外和小鼠模型中。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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