The effect of Inhaled Nicotine on Pulmonary Surfaces

吸入尼古丁对肺表面的影响

基本信息

批准号：
10089471
负责人：
Mehmet Kesimer
金额：
$ 55.72万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2017-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10089471
关键词：
Adhesions Adverse effects Affect Attenuated Biochemical Biophysics Blood - brain barrier anatomy Blood Circulation Brain Cardiovascular Diseases Cardiovascular system Cell Count Choline Chronic Bronchitis Chronic Obstructive Airway Disease Cone Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Dehydration Disease Disease Progression Down-Regulation Effectiveness Electronic cigarette Endoplasmic Reticulum Failure Flushing Functional disorder Health Human Hydration status Immunosuppression Impairment In Vitro Infection Inflammation Inhalation Ion Channel Gating Ion Transport Lead Ligands Link Liquid substance Lung Lung diseases Malignant neoplasm of lung Mediating MicroRNAs Microscopy Microspheres Mucins Mucous body substance Nicotine Outcome Pharmacology Phenotype Phosphoric Monoester Hydrolases Polymers Production Property Propylene Glycols Protein Dephosphorylation Proteins Proteome Public Health Resolution Respiratory syncytial virus Rheology Risk Route Signal Transduction Smoker Smoking Sodium Chloride Solid Structure Suggestion Surface System Techniques Testing Tobacco Viral Virus Virus Diseases Water absorption airway obstruction base bronchial epithelium electronic cigarette user immunosuppressed in vivo mass spectrometer mucus clearance nicotine exposure nicotine inhalation receptor respiratory infection virus respiratory virus response retrograde transport trafficking vegetable glycerin viscoelasticity

项目摘要

Nicotine is the pharmacologically active/addictive compound in tobacco. As such, the lung serves as an ideal and efficient delivery route for nicotine absorption into the bloodstream where it can then cross the blood brain barrier and induce psychotropic effects on the brain. Recently, with the advent of electronic cigarettes (E- Cigs), people have begun inhaling purified nicotine in a liquid vehicle (typically vegetable glycerin/propylene glycol). While the effects of nicotine on the brain and cardiovascular system are well known, the effects of nicotine on the lung have been less studied. Mucus clearance is a major part of the lung's innate defense system and represents the first point of contact of the body with inhaled nicotine. Perturbations in CFTR- mediated ion transport, which is required for mucus hydration/clearance, or biochemical alterations to mucins impair this system, leaving the lung more prone to mucus accumulation/plugging and viral infections, as evidenced by cystic fibrosis and chronic bronchitis lung disease. Our preliminary data indicate that E-cig users have a drastically altered mucus proteome which is suggestive of immunosuppression. In vitro, we found that nicotine, acting through intracellular Ca2+ (i) dephosphorylated CFTR leading to CFTR inactivation and internalization to the endoplasmic reticulum and (ii) altered mucin rheology by directly interacting with mucins. Furthermore, our data also suggest that the normal ability of the airways to activate CFTR and secrete mucins to generate an “airway flush” to remove inhaled viruses is impaired following nicotine exposure, which is predicted to lead to a failure to resolve common viral infections such as respiratory syncytial virus. We hypothesize therefore, that nicotine causes an immunosuppressed phenotype that leaves the lung more prone to viral exacerbations. Specifically, we propose that (i) nicotine-induced Ca2+ signaling leads to CFTR dephosphorylation and internalization to the endoplasmic reticulum (ii) altered mucus rheology and (iii) a failure to efficiently resolve viral infections. We shall study this hypothesis with the following specific aims: Aim 1. To test the hypothesis that nicotine, via increases in intracellular Ca2+, causes CFTR dephosphorylation and retrograde transport of CFTR to the ER that leads to ASL dehydration. Aim 2. To assess the impact of nicotine on mucin secretion, mucus/mucin biophysical and barrier properties, including their integrity, polymeric structure, and maturation. Aim 3. To determine the impact of inhaled nicotine on outcomes of respiratory virus infection in vivo.

尼古丁是烟草中具有药理活性/成瘾性的化合物，因此，肺是理想的选择。尼古丁吸收到血液中的有效输送途径，然后可以穿过血脑最近，随着电子烟（E-）的出现，对大脑产生了屏障和诱导精神作用。香烟），人们已经开始吸入液体载体（通常是植物甘油/丙烯）中的纯化尼古丁虽然尼古丁对大脑和心血管系统的影响众所周知，但尼古丁的影响尼古丁对肺部的影响研究较少。粘液清除是肺部先天防御的主要部分。系统并代表身体与 CFTR- 中吸入尼古丁扰动的第一个接触点。介导的离子运输，这是粘液水合/清除或粘蛋白生化改变所必需的损害该系统，使肺部更容易出现粘液积聚/堵塞和病毒感染，例如我们的初步数据表明，电子烟使用者患有囊性纤维化和慢性支气管炎肺部疾病。在体外，我们发现粘液蛋白质组发生了显着改变，表明存在免疫抑制。尼古丁，通过细胞内 Ca2+ 起作用 (i) 去磷酸化 CFTR 导致 CFTR 失活，内质网内化和（ii）通过与粘蛋白直接相互作用而实现粘蛋白流变学。此外，我们的数据还表明气道激活 CFTR 和分泌粘蛋白的正常能力接触尼古丁后，产生“气道冲洗”以清除吸入病毒的能力会受到损害，这是预计将导致无法解决呼吸道合胞病毒等常见病毒感染。因此，尼古丁会导致免疫抑制表型离开肺部具体来说，我们认为 (i) 尼古丁诱导的 Ca2+ 信号传导会导致病毒恶化。 CFTR 去磷酸化和内化至内质网 (ii) 粘液流变学和 (iii) 未能有效解决病毒感染问题，我们将通过以下具体目标来研究这一假设：目标 1. 检验尼古丁通过增加细胞内 Ca2+ 导致 CFTR 的假设 CFTR 去磷酸化和逆行转运至 ER，导致 ASL 脱水。目标 2. 评估尼古丁对粘蛋白分泌、粘液/粘蛋白生物物理和屏障的影响特性，包括其完整性、聚合结构和成熟度。目标 3. 确定吸入尼古丁对体内呼吸道病毒感染结果的影响。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tobacco exposure inhibits SPLUNC1-dependent antimicrobial activity.

烟草暴露会抑制 SPLUNC1 依赖性抗菌活性。

DOI：
10.1186/s12931-019-1066-2
发表时间：
2019
期刊：
Respiratory research
影响因子：
5.8
作者：
Moore,PatrickJ;Sesma,Juliana;Alexis,NeilE;Tarran,Robert
通讯作者：
Tarran,Robert

A modified fluorescent sensor for reporting glucose concentration in the airway lumen.

DOI：
10.1371/journal.pone.0254248
发表时间：
2021
期刊：
PloS one
影响因子：
3.7
作者：
Bearham J;Krutrök N;Lindberg B;Woodall M;Astrand A;Taylor JD;Biggart M;Vasiljevs S;Tarran R;Baines DL
通讯作者：
Baines DL

Reactive Oxygen Species, Mitochondrial Membrane Potential, and Cellular Membrane Potential Are Predictors of E-Liquid Induced Cellular Toxicity.

DOI：
10.1093/ntr/ntaa177
发表时间：
2020-12-15
期刊：
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco
影响因子：
0
作者：
Correia-Álvarez E;Keating JE;Glish G;Tarran R;Sassano MF
通讯作者：
Sassano MF

Loose ENDs: Electronic Nicotine Delivery Systems and the FDA's Recent Enforcement Policy.

松散的电子烟头：电子尼古丁输送系统和 FDA 的最新执法政策。