The effect of Inhaled Nicotine on Pulmonary Surfaces

吸入尼古丁对肺表面的影响

• 批准号: 9234295
• 负责人: Mehmet Kesimer
• 金额: $ 45.6万
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234295
• 关键词: Adhesions; Adverse effects; Affect; Attenuated; Biochemical; Biophysics; Blood - brain barrier anatomy; Blood Circulation; Brain; Breathing; 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; Epithelial; Failure; Flushing; Functional disorder; Gated Ion Channel; Glycerol; Health; Human; Hydration status; Immunosuppression; Impairment; In Vitro; Infection; Inflammation; 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; Vegetables; Viral; Virus; Virus Diseases; Water; absorption; airway obstruction; base; immunosuppressed; in vivo; mass spectrometer; receptor; respiratory infection virus; respiratory virus; response; retrograde transport; trafficking; 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.

尼古丁是烟草中的药物活性/成瘾化合物。因此，肺是理想的 且有效的递送途径将尼古丁滥用到血液中，然后可以跨越血液 障碍并引起对大脑的精神影响。最近，随着电子烟的冒险（e- CIGS），人们已经开始在液体车辆中吸入纯净的尼古丁（通常是蔬菜甘油/丙烯 糖）。虽然尼古丁对大脑和心血管系统的影响是众所周知的，但 肺上的尼古丁的研究较少。粘液清除是肺部天生防御的主要部分 系统，代表身体与遗传的接触点。 Cftr-扰动 介导的离子转运，这是粘液水合/清除率或对粘蛋白的生化改变所必需的 损害该系统，使肺部更容易粘液积聚/堵塞和病毒感染，因为 囊性纤维化和慢性支气管炎肺部疾病证明了这一点。我们的初步数据表明E-cig用户 具有巨大改变的粘液蛋白质组，暗示了免疫抑制。在体外，我们发现 尼古丁，通过细胞内Ca2+（i）去磷酸化的CFTR作用，导致CFTR失活和 内质网的内在化和（ii）通过直接与粘蛋白相互作用改变了粘蛋白流变学。 此外，我们的数据还表明，气道激活CFTR和秘密粘蛋白的正常能力 在尼古丁暴露后，要产生“气道冲洗”以去除遗传病毒会受到损害， 预计导致无法解决常见病毒感染，例如呼吸道合胞病毒。我们 因此，假设尼古丁引起的免疫抑制表型离开肺 更容易病毒加重。具体而言，我们建议（i）尼古丁诱导的Ca2+信号传导导致 CFTR去磷酸化和内质网的内在化（II）改变了粘液流变学和（III）A 无法有效解决病毒感染。我们将以以下具体目的研究这一假设： 目的1。为了测试尼古丁通过细胞内Ca2+增加的假设引起CFTR CFTR向ER的去磷酸化和逆行转运，导致ASL脱水。 目标2。评估尼古丁对粘蛋白分泌的影响，粘液/粘蛋白生物物理和障碍物 特性，包括其完整性，聚合结构和成熟。 目标3。确定遗传尼古丁对体内呼吸道病毒感染预后的影响。