How nicotine delivered by Electronic Nicotine Delivery Systems (ENDS) affects the lung and its recovery from cigarette smoking

电子尼古丁输送系统 (ENDS) 输送的尼古丁如何影响肺部及其从吸烟中的恢复

• 批准号: 10618951
• 负责人: Noel G. Carlson
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618951
• 关键词: Address; Affect; Alveolar; Alveolar Macrophages; Animal Experiments; Calcium; Cells; Chemicals; Collagen; Deposition; Disease; Electronic Nicotine Delivery Systems; Eotaxin; Exposure to; Fibrosis; Gene Expression; Genetic Transcription; Glycerol; Health; Health system; Heating; House Dust Mite Allergens; Immune; Immune response; Immunology; In Vitro; Inhalation; Interleukin-10; Interleukin-4; Investigation; Ion Channel; Kinetics; Liquid substance; Lung; Macrophage Activation; Measurement; Measures; Methods; Morphology; Mucins; Mus; Mutation; Nicotine; Nicotinic Receptors; Pharmaceutical Preparations; Polyethylene Glycols; Process; Production; Pyroglyphidae; RNA; Recovery; Recovery of Function; Reproducibility; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Route; Salts; Sentinel; Signal Pathway; Signal Transduction; Smoking; Sodium Chloride; Specificity; System; Tissues; Vegetables; Veterans; aerosolized; base; chemokine; cigarette smoke; cigarette smoking; cytokine; design; electronic liquid; eosinophil; experience; experimental study; exposure to cigarette smoke; immune function; immunoregulation; inhibitor; lung injury; modifiable risk; nicotine exposure; nicotine self-administration; nicotine use; positive allosteric modulator; pulmonary function; rapid growth; receptor; response; smoking cessation; smoking exposure; transcriptome sequencing; treatment response; uptake; vaping; vaporization

Since their introduction to the marketplace, Electronic Nicotine Delivery Systems (ENDS) have experienced a rapid growth in popularity as a means to deliver nicotine to the user in unprecedented high concentrations and purity. There is little evidence pertaining to the consequences this route of nicotine self- administration has on the health of the naïve user or those who use this product to aid in cigarette smoking (CS) cessation. This Merit application is designed to fill gaps in our understanding of these issues. Here the focus will be on how the lung morphology and normal gene expression including a defined response to the inhaled house dust mite allergen is impacted by ENDS:nic exposure, especially in the lung previously exposed to cigarette smoke. There are 3 interactive Aims to address the Project Hypothesis: The use of nicotine as delivered by electronic nicotine delivery systems (ENDS:nic), both in the naïve lung and subsequent to cessation of cigarette smoking (CS), impacts the morphology and immune responsiveness of the exposed lung and complicates normal recovery processes following CS cessation. Specific Aim 1. Does ENDS:nic exposure impact lung morphology, mucin production and fibrosis in the naïve lung and the lung previously damaged by CS exposure? Measurement of ENDS:nic effects on the lung will include morphologic changes in alveolar spaces, mucin production (e.g., Muc5b) and deposition, and changes to collagen deposition (fibrosis). Results will determine how the form of nicotine (salt versus free-base) and its relative concentrations impact these parameters. We further hypothesize that ENDS:nic exposure (and possibly carrier alone) will alter lung morphology and that mice previously exposed to CS will not recover to the same extent as mice that are allowed to recover in the absence of END:nic use and possibly carrier. Specific Aim 2. Does ENDS:nic impact immune function in naïve mice and does the transition from cigarette smoke to ENDS:nic exposure impede immune functional recovery? ENDS:Nic delivery strongly suppresses the lung eosinophil response to inhalation of the common house dust mite (HDM) allergen. This reliable experimental measurement provides an end-point to quantify the impact by different ionic forms of nicotine, their concentration and the associated e- liquid carrier compounds. The focus will also be on transcriptional responsiveness to HDM by AM and specific lung cellular signaling responses during recovery from prior CS-associated damage in the context of ENDS:nic relative to no product use as well as the impact by ENDS:nic itself. Specific Aim 3. How are alpha7-modulated cell-signaling mechanisms in the alveolar macrophage (AM) affected by ENDS:nic exposure? These experiments will focus on alveolar macrophages (AM) which constitute the majority of immune cells in the bronchial alveolar lung fluids (BALF). Newly developed methods that combine AM enrichment from the BALF of ENDS:nic and CS exposed mice and in vitro response to treatment with defined cytokines (IL-4+IL-10) will be done in the presence of specific inhibitors of cell signaling intermediates and positive allosteric modulators of the AM target of nicotine, the nicotinic receptor alpha7. The AM transcriptional response mechanisms will be measured using RT-PCR as well as RNA-Seq. Collectively, this study will provide the first comprehensive view of AM responsiveness after ENDS:nic exposure and how ENDS:nic use impacts the lung during recovery from previous cigarette smoking.

自推出市场以来，电子尼古丁递送系统(END)已经 经历了快速增长的受欢迎程度，作为向用户提供尼古丁的一种手段，达到了前所未有的高度 浓度和纯度。几乎没有证据表明这种尼古丁自我释放途径的后果。 政府对天真的使用者或使用本产品帮助吸烟的人的健康有影响(CS) 停止。这个Merit应用程序旨在填补我们对这些问题的理解空白。这里的焦点是 将关于肺的形态和正常的基因表达，包括对吸入的明确反应 屋尘螨变应原受END：NIC暴露的影响，特别是在先前暴露于 香烟味。有三个互动目标来解决项目假说：尼古丁的使用 通过电子尼古丁递送系统(结束：NIC)，在幼稚的肺和在停止 吸烟(CS)，影响暴露肺的形态和免疫反应性 使CS停止后的正常恢复过程复杂化。具体目标1.目标：NIC暴露 对肺形态、粘蛋白产生和幼稚肺及肺纤维化的影响 因接触CS而受损？末梢的测量：NIC对肺的影响将包括形态变化 在肺泡腔，粘蛋白的产生(如MUC5B)和沉积，以及胶原沉积的变化(纤维化)。 结果将决定尼古丁的形式(盐与游离碱)及其相对浓度如何影响 这些参数。我们进一步假设：NIC暴露(可能是单独的携带者)会改变肺部 形态，先前暴露于CS的小鼠不会恢复到与允许的小鼠相同的程度 在没有结束的情况下恢复：网卡使用和可能的运营商。具体目标2.结束：NIC的影响 幼稚小鼠的免疫功能和从吸烟到吸烟的转变：NIC暴露 阻碍免疫功能恢复？结束：NIC传递强烈抑制肺嗜酸性粒细胞反应 吸入常见的屋尘螨(HDM)变应原。这一可靠的实验测量提供了 一个终点，用来量化不同离子形式的尼古丁的影响，它们的浓度和相关的e- 液体载体化合物。重点还将放在AM和特定基因对HDM的转录反应上 在END：NIC的情况下，从先前CS相关损伤中恢复期间的肺细胞信号反应 相对于不使用产品以及终端的影响：NIC本身。具体目标3.字母7是如何调制的 END影响肺泡巨噬细胞(AM)的细胞信号机制：NIC暴露？这些 实验将集中在肺泡巨噬细胞(AM)上，它构成了免疫系统中的大多数细胞 肺泡灌洗液(BALF)。新开发的方法结合了从BALF中提取AM的浓缩 结果：NIC和CS暴露的小鼠，对特定细胞因子(IL-4+IL-10)治疗的体外反应将是 在特定的细胞信号中间体抑制剂和正变构调节剂存在的情况下进行 我是尼古丁的靶子，尼古丁受体α7。AM转录反应机制将是 用RT-PCR和RNA-Seq法检测。 总而言之，这项研究将提供有关AM在结束后的响应能力的第一个全面视图：NIC 暴露和如何结束：在戒烟恢复期间，NIC的使用会影响肺部。