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

摘要 这项申请是对促进炎症基础和应用研究的想法的回应 解决方案，特别是NIEHS对与环境暴露有关的炎症解决方案的兴趣。它是 越来越多的人认识到，对炎性刺激的免疫反应涉及到专门的亲- 分解介质(SPM)通过分解细胞和组织来协调肺内环境的恢复 发炎。然而，关于PM2.5对人体的影响的数据很少，PM2.5是一种无处不在的空气 污染物，对SPM和炎症消解。这与大量关于 PM2.5的促炎反应。这里我们假设PM2.5损害了细胞的生物合成和动力学 SPMS，导致呼吸道炎症消退受阻。因为呼吸道炎症是 哮喘，这是很有可能的，但尚未得到证实，哮喘患者的解决能力较差 污染引起的炎症。没有数据支持炎症的性别特异性假说 解决，尽管已知的性别差异的促炎反应空气污染。因此，我们进一步 假设PM2.5对炎症消退的影响在哮喘和非哮喘患者中有所不同 在男人和女人之间。我们建议通过以下方式在翻译研究框架中检验这些假设 利用现有的关于空气污染对健康影响的小组研究。我们的方法包括体外细胞培养 侧重于SPM生物合成和拆分动力学的分子机制的实验(目标1)和一个小组 旨在检查SPM-PM2.5在体内的关系的研究(目标2)，并检查SPM可能介导的 PM2.5对临床结果的影响(目标3)。在AIM中最大限度地提高机械性发现的可译性 1，我们将使用从小组研究参与者中收集的原代呼吸道上皮细胞，并将使用 在参与者居住的英国伦敦收集的PM2.5成分特征。在AIM 2小组研究中，40 患有哮喘和无哮喘的40名参与者将被纵向测量4次鼻液中的SPM和 诱导痰，分别代表进入PM2.5的第一个入口和肺部。详细的个人PM2.5 SPM前几小时至几天特定来源PM2.5组分的剂量和内剂量(生物标志物) 测量结果将与痰和鼻腔SPM浓度相关联。我们预计会看到不同之处 在时间-浓度分布中，分别由哮喘和性别决定。在目标3中，通过利用专家小组研究的丰富 关于具有临床相关性的健康结果的数据集，我们将检查SPM对暴露- 在AIMS 1和AIMS中确定的炎症和消退反应的关键时间点的结果关联 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 PM2.5的动力学和临床相关的功能和炎症反应。这项研究将产生真实的生活 更好地了解SPM在解决哮喘患者呼吸道污染引起的炎症中的作用的数据 与非哮喘患者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