TRP-mediated airway inflammation by e-cigarette vaping

项目摘要 电子烟被认为比吸烟毒性更小， 像皇家医师学院这样的医师团体推荐使用电子烟作为戒烟的一种方式 吸烟是一种降低风险的方法。然而，这样的建议可能会被误解为意味着电子烟 对健康没有不良影响，尤其是对以前从不吸烟的人。为了支持这一观点，惊人的11% 从不吸烟的高中生中有30%承认持续吸烟。不幸的是， 电子烟危害的证据，包括慢性支气管炎的发展。因此， 需要探索从不吸烟者，特别是弱势青少年人群的电子烟。为此， 本申请研究电子烟蒸气如何不利地影响人的气道。需要建立的数据 哪些电子烟成分是最有害的-尼古丁，vaping流体或添加的合成香料-以及如何 它们机械地在吸入的主要目标部位即气道上皮发挥作用。到 为了回答这些问题，我们组建了一个具有气道生物学专业知识的多学科团队， 电子烟蒸汽影响气道健康的程度。我们将研究电子烟蒸气对气道的影响 体外上皮细胞（aim 1），在一个新的绵羊，大动物模型（aim 2）中的粘膜纤毛功能，以及在一个交叉 开始使用vape的年轻从不吸烟者的截面队列（目的3）。后者的电子烟用户则在 伤害的最大风险。目的1将机械地检查电子烟蒸气在气道的信号通路 上皮，触发TRP受体刺激TGF-β 1和Notch信号传导， 慢性支气管炎的标志性症状这一目标将通过暴露完全不同的 使用先进的暴露机器人，在体外将气道上皮细胞暴露于电子烟蒸气及其成分。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， 的蒸汽成分对粘膜纤毛功能的参数和调查气道炎症。最后，目标3 将检查不吸烟的年轻人的粘膜纤毛功能障碍和气道炎症的参数， 开始使用横截面设计vape至少6个月。蒸汽和地形的历史将是 以客观的方式进行评估，以与结果相关联。因此，该应用程序将机械地检查 电子烟蒸汽对气道功能和炎症的有害影响，从 从实验台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.