Molecular Mechanisms for Resolving Air Pollution Induced Pulmonary Inflammation: Potential Differences by Asthma and Sex (RAPIDAS)

摘要 本申请是响应国家科学院促进炎症基础和应用研究 分辨率，特别是NIEHS对与环境暴露相关的炎症分辨率的兴趣。是 越来越多的人认识到，对炎症刺激的免疫反应涉及专门的促炎症反应， 通过分解细胞和组织，协调肺恢复稳态的分解介质（SPM） 炎症然而，关于PM2.5（一种无处不在的空气）对人体的影响， 污染物，对SPM和炎症的解决。这与大量的文献形成鲜明对比， 对PM2.5的促炎反应。在这里，我们假设PM2.5损害细胞生物合成和动力学， SPM，导致气道炎症消退受损。由于气道炎症是 哮喘，这是非常合理的，但尚未得到证实，哮喘患者的解决能力较低， 污染引起的炎症没有数据支持炎症的性别特异性假说 尽管已知对空气污染的促炎反应存在性别差异，但这一问题仍然存在。因此，我们进一步 假设PM2.5对炎症消退的影响在患有哮喘和没有哮喘的人之间不同， 男人和女人之间。我们建议在一个翻译研究的框架中检验这些假设， 利用现有的空气污染健康影响小组研究。我们的方法包括体外细胞培养 实验侧重于SPM生物合成和拆分动力学的分子机制（目标1）和一个小组 一项旨在研究SPM-PM2.5在体内的关系（目的2），并研究潜在的SPMs介导的 PM2.5对临床结果的影响（目标3）。为了最大限度地提高Aim中的机械发现的可翻译性 1，我们将使用从小组研究参与者中收集的原代气道上皮细胞， 在参与者居住的英国伦敦收集的以成分为特征的PM2.5。在目标2小组研究中，40 患有哮喘的参与者和40名没有哮喘的参与者将纵向测量4次鼻液中的SPM， 诱导痰，分别代表PM2.5进入的第一入口和肺。详细PM2.5 SPM前数小时至数天的源特异性PM2.5成分的剂量和内部剂量（生物标志物） 测量结果将与痰和鼻SPM浓度相关。我们期待看到差异 在时间-浓度曲线中，分别按哮喘和性别列出。在目标3中，通过利用小组研究丰富的 临床相关的健康结果数据集，我们将研究SPM对暴露的介导作用- 目的1中确定的炎症和消退反应关键时间点的结局相关性， 2.综上所述，我们期望将调节SPM生物合成的分子机制与分辨率联系起来， 动力学和临床相关的功能和炎症反应PM2.5。这项研究将产生现实生活中 数据，以更好地了解SPM在解决哮喘患者气道中污染诱导的炎症中的作用 与非哮喘患者的对比以及男性与女性的对比。 1

ABSTRACT This application is in response to the NOSI of Promoting Fundamental and Applied Research in Inflammation Resolution, in particular to NIEHS’ interest in inflammation resolution related to environmental exposure. It is increasingly recognized that the immune response to an inflammatory stimulus involves specialized pro- resolving mediators (SPMs) that orchestrate the lung’s return to homeostasis by resolving cellular and tissue inflammation. However, little data in humans are available concerning the effects of PM2.5, a ubiquitous air pollutant, on SPMs and inflammation resolution. This is in marked contrast to the large body of literature on the proinflammatory response to PM2.5. Here we hypothesize that PM2.5 impairs cellular biosynthesis and kinetics of SPMs, leading to compromised resolution of inflammation in the airway. As airway inflammation is a hallmark of asthma, it is highly plausible but yet to be confirmed that individuals with asthma are less capable of resolving pollution-induced inflammation. No data are available to support a sex-specific hypothesis on inflammation resolution, despite the known sex-difference in proinflammatory responses to air pollution. Hence, we further hypothesize the effects of PM2.5 on inflammation resolution differ between people with and without asthma and between men and women. We propose to test these hypotheses in a translational study framework by leveraging an existing panel study of air pollution health effects. Our approach comprises of ex vivo cell culture experiments focusing on molecular mechanisms of SPM biosynthesis and resolution kinetics (Aim 1) and a panel study aiming to examine SPM-PM2.5 relationships in vivo (Aim 2) and to examine potential SPMs mediation of the PM2.5 effects on clinical outcomes (Aim 3). To maximize the translatability of the mechanistic findings in Aim 1, we will use primary airway epithelial cells collected from among the panel study participants and will use composition-characterized PM2.5 collected in London, UK, where participants reside. In Aim 2 panel study, 40 participants with and 40 without asthma will be measured 4 times longitudinally for SPMs in nasal fluid and induced sputum, representing the first portal of PM2.5 entry and the lung, respectively. Detailed personal PM2.5 doses and internal doses (biomarkers) of source-specific PM2.5 constituents hours to days prior to SPM measurements will be associated with sputum and nasal SPM concentrations. We anticipate to see differences by asthma and sex, respectively, in the time-concentration profile. In Aim 3, by leveraging the panel study’s rich dataset on health outcomes of clinical relevance, we will examine the mediating effects of SPMs on the exposure- outcome associations at the key time-points of inflammatory and resolution responses identified in Aims 1 and 2. Taking all together, we anticipate to link molecular mechanisms regulating SPM biosynthesis with resolution kinetics and clinically-relevant functional and inflammatory responses to PM2.5. The study will generate real-life data to better understand the role of SPM in resolving pollution-induced inflammation in the airways of asthmatics versus non-asthmatics and those of men versus women. 1