The effect of Inhaled Nicotine on Pulmonary Surfaces

尼古丁是烟草中具有药理活性/成瘾性的化合物。因此，肺是一种理想的 以及尼古丁吸收到血液中的有效传递途径，然后它可以穿过血脑 对大脑产生阻隔和诱导精神作用。最近，随着电子烟(电子烟)的出现， 香烟)，人们已经开始在液体交通工具(通常是植物甘油/丙烯)中吸入纯化的尼古丁 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 尼古丁对肺部的影响研究较少。粘液清除是肺固有防御的主要部分 它代表了人体与吸入尼古丁的第一个接触点。CFTR中的摄动- 介导的离子转运，这是粘液水合/清除所必需的，或者是粘蛋白的生化变化 损害这一系统，使肺更容易粘液堆积/堵塞和病毒感染，如 表现为囊性纤维化和慢性支气管炎肺部疾病。我们的初步数据显示，电子烟用户 有一个明显改变的粘液蛋白质组，这表明免疫抑制。在体外，我们发现 尼古丁通过细胞内Ca~(2+)去磷酸化CFTR，导致CFTR失活和 内化到内质网；(Ii)通过直接与粘蛋白相互作用改变粘蛋白的流变性。 此外，我们的数据还表明，正常的呼吸道激活cftr和分泌粘蛋白的能力 尼古丁暴露后，产生“呼吸道冲洗”以清除吸入病毒的能力受到损害，这是 预计将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，假设尼古丁导致一种免疫抑制的表型离开肺 更容易出现病毒恶化。具体地说，我们提出：(I)尼古丁诱导的钙信号导致 Cftr去磷酸化和内化内质网(Ii)改变粘液流变性和(Iii)a 未能有效解决病毒感染问题。我们将以以下具体目标来研究这一假设： 目的1.验证尼古丁通过增加细胞内钙离子而引起CFTR的假设 Cftr去磷酸化和逆行转运到内质网，导致ASL脱水。 目的2.评价尼古丁对粘蛋白分泌、粘液/粘蛋白生物物理和屏障的影响 性能，包括其完整性、聚合物结构和成熟度。 目的3.确定吸入尼古丁对体内呼吸道病毒感染结局的影响。

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.