The effect of Inhaled Nicotine on Pulmonary Surfaces

吸入尼古丁对肺表面的影响

• 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
• 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

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.

尼古丁是烟草中的活性/成瘾化合物。因此，肺作为理想的 以及尼古丁吸收到血液中的有效输送途径，然后它可以穿过血脑 屏障并对大脑产生精神影响。最近，随着电子烟（E- 2000年），人们开始吸入液体载体（通常是植物甘油/丙烯）中的纯化尼古丁 乙二醇）。虽然尼古丁对大脑和心血管系统的影响是众所周知的，但尼古丁对大脑和心血管系统的影响是显而易见的。 尼古丁对肺部的影响研究较少。粘液清除是肺的先天防御的主要部分 尼古丁是人体与吸入尼古丁的第一个接触点。CFTR中的扰动- 介导的离子转运，这是粘液水合/清除或粘蛋白生化改变所必需的 损害这一系统，使肺更容易发生粘液积聚/堵塞和病毒感染， 由囊性纤维化和慢性支气管炎肺病证实。我们的初步数据表明，电子烟用户 粘液蛋白质组有很大的改变，这暗示了免疫抑制。在试管中，我们发现， 尼古丁，通过细胞内Ca 2+起作用（i）去磷酸化CFTR，导致CFTR失活， 内质网的内化和（ii）通过直接与粘蛋白相互作用改变粘蛋白流变学。 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， 产生“气道冲洗”以清除吸入的病毒的能力在尼古丁暴露后受损， 预计会导致无法解决常见的病毒感染，如呼吸道合胞病毒。我们 因此，假设尼古丁引起免疫抑制表型， 更容易出现病毒恶化具体而言，我们提出（i）尼古丁诱导的Ca 2+信号转导导致 CFTR去磷酸化和内质网内化（ii）改变粘液流变学和（iii） 未能有效解决病毒感染。我们将以下列具体目标来研究这一假说： 目标1.检验尼古丁通过细胞内Ca 2+增加导致CFTR的假设 CFTR去磷酸化和逆行转运到ER，导致ASL脱水。 目标二。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 性质，包括其完整性、聚合物结构和成熟度。 目标3.确定吸入尼古丁对体内呼吸道病毒感染结局的影响。

项目成果

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
• 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。

• 发表时间: 2020
• 期刊: European medical journal. Respiratory
• 作者: Ahmad,Saira;Sassano,MFlori;Tarran,Robert
• 通讯作者: Tarran,Robert

E-cigarette constituents propylene glycol and vegetable glycerin decrease glucose uptake and its metabolism in airway epithelial cells in vitro.

• DOI: 10.1152/ajplung.00123.2020
• 发表时间: 2020-12-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Woodall M;Jacob J;Kalsi KK;Schroeder V;Davis E;Kenyon B;Khan I;Garnett JP;Tarran R;Baines DL
• 通讯作者: Baines DL