TRP-mediated airway inflammation by e-cigarette vaping

电子烟引起的 TRP 介导的气道炎症

• 批准号: 10247032
• 负责人: Matthias A Salathe
• 金额: $ 44.96万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247032
• 关键词: Acute; Adolescent; Adverse effects; Affect; Animal Model; Animals; Apical; Belief; Biology; CLCA2 gene; Cell membrane; Cells; Chronic; Chronic Bronchitis; Cinnamon - dietary; Complement; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Electronic cigarette; Epithelial Cells; Exposure to; Flavoring; Functional disorder; Goblet Cells; Habits; Harvest; Health; High School Student; Human; Hyperplasia; Immune response; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inhalation; Ion Channel; Knowledge; Liquid substance; MAP Kinase Gene; Mediating; Menthol; Metaplastic Cell; Mucociliary Clearance; Mucous body substance; Nasal Epithelium; Nicotine; Nicotinic Receptors; Nose; Outcome; Pathway interactions; Physicians; Population; Propylene Glycols; Public Health; Recommendation; Recording of previous events; Reporting; Research; Risk; Risk Reduction; Robot; Science; Sheep; Signal Pathway; Signal Transduction; Site; Smoke; Smoking; System; TRP channel; TRPA channel; Testing; Tobacco; Tobacco smoking behavior; Transforming Growth Factor alpha; Transforming Growth Factor beta; Vulnerable Populations; airway epithelium; airway inflammation; airway surface liquid; base; bronchial epithelium; cell injury; cohort; college; cytokine; design; e-cigarette aerosols; electronic cigarette use; electronic cigarette user; electronic liquid; electronic vape; human subject; in vivo; mucus hypersecretion; multidisciplinary; never smoker; never smoking; nicotine use; nicotine vapor; non-smoker; non-smoking; notch protein; novel; p38 Mitogen Activated Protein Kinase; patient population; receptor; translational study; vaping; vapor; vegetable glycerin; vulnerable adolescent

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.

项目概要 人们认为，电子烟（e-cigs）的毒性比吸食烟草的毒性要小，因此 皇家内科医师学院等医生团体建议使用电子烟作为戒烟的一种方式 以降低风险的方式吸烟。然而，这样的建议可能会被误解为暗示电子烟已经 对健康没有不良影响，特别是对于以前从不吸烟的人。令人惊讶的是，有 11% 的人支持这一观点 从不吸烟的高中生中，有 1% 的人承认自己一直在吸电子烟。不幸的是，越来越多 电子烟危害的证据，包括慢性支气管炎的发展。因此，潜在的损害 需要探索向从不吸烟者，特别是弱势青少年人群吸电子烟。为此， 该应用程序检查电子烟蒸汽如何对人体呼吸道产生不利影响。数据需要建立 哪些电子烟成分最有害——尼古丁、电子烟液或添加的合成香料——以及如何危害 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来研究 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（目标 1）、新绵羊、大型动物模型中的粘膜纤毛功能（目标 2）以及交叉研究 开始吸电子烟的年轻从不吸烟者群体（目标 3）。后一组电子烟用户位于 最大的伤害风险。目标 1 将机械地检查气道中电子烟蒸汽的信号传导途径 上皮细胞，触发 TRP 受体刺激 TGF-b1 和 Notch 信号传导，引起粘液纤毛 功能障碍，慢性支气管炎的标志。这一目标将通过暴露完全差异化来实现 使用复杂的暴露机器人在体外将气道上皮细胞暴露于电子烟蒸汽及其成分。目标2将 确认在新的绵羊大型动物模型中体外研究的机制，该模型可以检查其影响 蒸气成分对粘膜纤毛功能参数的影响并研究气道炎症。最后，目标3 将检查年轻不吸烟者的粘液纤毛功能障碍和气道炎症参数 使用横截面设计开始使用电子烟至少 6 个月。电子烟和地形的历史将是 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 在团队科学方法中，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。

项目成果

SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice.

• DOI: 10.1073/pnas.2302083120
• 发表时间: 2023-08-29
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Alhammad, Yousef M.;Parthasarathy, Srivatsan;Ghimire, Roshan;Kerr, Catherine M.;O'Connor, Joseph J.;Pfannenstiel, Jessica J.;Chanda, Debarati;Miller, Caden A.;Baumlin, Nathalie;Salathe, Matthias;Unckless, Robert L.;Zuniga, Sonia;Enjuanes, Luis;More, Sunil;Channappanavar, Rudragouda;Fehr, Anthony R.
• 通讯作者: Fehr, Anthony R.

Fibroblast growth factor 23 and Klotho contribute to airway inflammation.

• DOI: 10.1183/13993003.00236-2018
• 发表时间: 2018-07
• 期刊: The European respiratory journal
• 作者: Krick S;Grabner A;Baumlin N;Yanucil C;Helton S;Grosche A;Sailland J;Geraghty P;Viera L;Russell DW;Wells JM;Xu X;Gaggar A;Barnes J;King GD;Campos M;Faul C;Salathe M
• 通讯作者: Salathe M

Nebulized Menthol Impairs Mucociliary Clearance via TRPM8 and MUC5AC/MUC5B in Primary Airway Epithelial Cells.

• DOI: 10.3390/ijms24021694
• 发表时间: 2023-01-15
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Baumlin, Nathalie;Silswal, Neerupma;Dennis, John S.;Niloy, Asef J.;Kim, Michael D.;Salathe, Matthias
• 通讯作者: Salathe, Matthias

Rebuttal from Samuel Chung, Charles D. Bengtson, Michael D. Kim and Matthias Salathe.

• DOI: 10.1113/jp280093
• 发表时间: 2020-08
• 期刊: The Journal of physiology
• 作者: Chung S;Bengtson CD;Kim MD;Salathe M
• 通讯作者: Salathe M

A long noncoding RNA antisense to ICAM-1 is involved in allergic asthma associated hyperreactive response of airway epithelial cells.

• DOI: 10.1038/s41385-020-00352-9
• 发表时间: 2021-05
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Devadoss D;Daly G;Manevski M;Houserova D;Hussain SS;Baumlin N;Salathe M;Borchert GM;Langley RJ;Chand HS
• 通讯作者: Chand HS