TRP-mediated airway inflammation by e-cigarette vaping

项目摘要 “电子烟”(e-cigs)的毒性被认为比吸烟的烟草要小， 英国皇家医师学会等医生团体建议使用电子烟作为戒烟方法 以一种降低风险的方法吸烟。然而，这样的建议可能会被误解为暗示蒸发具有 对健康没有不良影响，特别是对以前从不吸烟的人。支持这一观点的人达到了惊人的11% 从不吸烟的高中生中，有1%的人承认经常吸电子烟。不幸的是，有越来越多的 蒸发造成伤害的证据，包括慢性支气管炎的发展。因此，潜在的损害是 需要探索向从不吸烟的人，特别是脆弱的青少年人口提供电子烟。为此， 这个应用程序检查了电子烟蒸气如何对人类呼吸道产生不利影响。数据需要建立 哪种电子烟成分最有害--尼古丁、蒸发液或添加的合成香料--以及如何 它们在吸入的主要目标部位，即呼吸道上皮，机械地发挥作用。至 回答这些问题，我们组建了一个具有呼吸道生物学专业知识的多学科团队来研究 电子烟蒸气对呼吸道健康的影响程度。我们将研究电子烟蒸气对呼吸道的影响 体外上皮细胞(Aim 1)，对新的绵羊大动物模型粘液纤毛功能的影响(Aim 2)，以及在一个新的绵羊大动物模型(Aim 2)中 开始吸食电子烟的年轻从不吸烟者的分区队列(目标3)。后一类电子核证服务使用者的网址为 最大的伤害风险。目标1将从机械角度研究e-cig蒸气在呼吸道的信号通路。 上皮细胞，触发色氨酸受体刺激转化生长因子-β1和Notch信号导致粘液纤毛 功能障碍，慢性支气管炎的标志。这一目标将通过揭露完全差异化的 使用复杂的暴露机器人将体外培养的呼吸道上皮细胞转化为e-CIG蒸气及其组分。目标2将 在一种新的绵羊大型动物模型中证实了体外研究的机制，该模型允许检查这种作用 观察蒸气成分对粘液纤毛功能参数的影响，并研究呼吸道炎症。最后，目标3 将检测从不吸烟的年轻吸烟者的粘液纤毛功能障碍和呼吸道炎症参数 开始使用横截面设计至少6个月的VAPE。汽化和地形的历史将是 以客观的方式进行评估，以便与结果相关联。因此，该应用程序将机械地检查 电子烟蒸气对呼吸道功能和炎症的有害影响 从板凳到动物模型再到人类受试者。

Project Summary Vaping” electronic cigarettes (e-cigs) is believed to be less toxic than smoking tobacco, leading the physician groups such as the Royal College of Physicians to recommended e-cig use as a way to quit tobacco smoking in a risk reduction approach. Such advice, however, may be misinterpreted to imply that vaping has no ill effects upon health, especially for previous never-smokers. In support of this notion, an astonishing 11% percent of never smoking high school students admit to consistent vaping. Unfortunately, there is growing evidence of harm from vaping, including the development of chronic bronchitis. Thus, the potential damage of vaping to never smokers, especially the vulnerable adolescent population, needs to be explored. To this end, this application examines how e-cigarette vapors adversely impact human airways. Data need to establish which e-cig components are most harmful – nicotine, the vaping fluid, or added synthetic flavors – and how they mechanistically exert their effects at the primary target site of inhalation, namely the airway epithelium. To answer these questions, we assembled a multidisciplinary team with expertise in airway biology to study the extent by which e-cig vapor affects airway health. We will investigate the effect of e-cig vapor on airway epithelia in vitro (aim 1), on mucociliary function in a new ovine, large animal model (aim 2), and in a cross- sectional cohort of young never smokers who started to vape (aim 3). The latter group of e-cig users is at greatest risk for harm. Aim 1 will mechanistically examine the signaling pathway of e-cig vapor at the airway epithelium, triggering TRP receptors to stimulate TGF-b1 and Notch signaling to cause mucociliary dysfunction, a hallmark of chronic bronchitis. This aim will be accomplished by exposing fully differentiated airway epithelial cells in vitro to e-cig vapor and its components using sophisticated exposure robots. Aim 2 will confirm the mechanisms studied in vitro in a new, ovine large animal model that allows to examine the effects of vapor components on parameters of mucociliary function and investigate airway inflammation. Finally, aim 3 will examine parameters of mucociliary dysfunction and airway inflammation in young never smokers who started to vape for at least 6 months using a cross sectional design. History of vaping and topography will be assessed in objective ways to correlate with outcomes. This application will therefore mechanistically examine harmful effects of e-cig vapor on airway function and inflammation in a team science approach, going from bench to animal model to human subjects.