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

解决空气污染引起的肺部炎症的分子机制：哮喘和性别的潜在差异（RAPIDAS）

• 批准号: 10718525
• 负责人: JUNFENG ZHANG
• 金额: $ 54.95万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718525
• 关键词: Adult; Affect; Age; Air; Air Pollutants; Air Pollution; Anabolism; Animals; Anti-Inflammatory Agents; Applied Research; Asthma; Biological Markers; CD59 Antigen; Cell Culture Techniques; Cells; Chemicals; Clinical; Coculture Techniques; Collecting Cell; DNA Methylation; Data; Data Set; Disease; Dose; Environmental Exposure; Epithelial Cells; Exposure to; Genes; Genetic Transcription; Health; Homeostasis; Hour; Human; Immune response; Impairment; In Vitro; Individual; Inflammation; Inflammation Process; Inflammatory; Inflammatory Response; Inhalation; Intervention; Investigation; Kinetics; Knowledge; Life; Link; Lipoxins; Liquid substance; Literature; London; Lung; Measurement; Measures; Mediating; Mediation; Mediator; Molecular; Nasal Epithelium; National Institute of Environmental Health Sciences; Nose; Observational Study; Outcome; Oxidative Stress; Participant; Pathway interactions; Persons; Pharmaceutical Preparations; Pollution; Predisposition; Protocols documentation; Pulmonary Inflammation; Resolution; Respiratory System; Role; Sample Size; Sex Differences; Signal Transduction; Site; Source; Sputum; Stimulus; Symptoms; Testing; Time; Tissues; Woman; airway epithelium; airway inflammation; asthma exacerbation; asthmatic; asthmatic airway; chronic inflammatory disease; clinically relevant; epigenetic profiling; epigenetic regulation; experimental study; fine particles; fundamental research; in vivo; interest; men; neutrophil; novel; prevent; pulmonary function; response; sex; transcriptome sequencing; translational approach; translational study; urinary

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

抽象的 该应用是响应促进炎症基础和应用研究的NOSI 解决方案，尤其是NIEHS对与环境暴露有关的炎症解决方案的兴趣。这是 越来越认识到对炎症刺激的免疫反应涉及专业的促进 通过解决细胞和组织来解决肺部恢复到体内平衡的介体（SPM） 炎。但是，人类几乎没有关于无处不在的空气的影响的人类数据 污染物，SPM和炎症分辨率。这与大量文献形成鲜明对比 对PM2.5的促炎反应。在这里，我们假设PM2.5会损害细胞生物合成和动力学 SPM，导致气道中炎症的分辨率损害。由于气道炎症是 哮喘，这是高度合理的，但尚未得到证实，哮喘患者的能力较低 污染引起的炎症。没有数据可以支持针对炎症的性别特定假设 解决方案，尽管对空气污染的促炎反应有已知的性别差异。因此，我们进一步 假设PM2.5对患有和没有哮喘和哮喘患者之间炎症分辨率的影响 在男人和女人之间。我们建议在翻译研究框架中检验这些假设 利用现有的空气污染健康效应研究。我们的方法包括离体细胞培养 针对SPM生物合成和分辨率动力学的分子机制的实验（AIM 1）和一个面板 研究旨在检查体内的SPM-PM2.5关系（AIM 2），并检查潜在的SPMS介导 PM2.5对临床结果的影响（AIM 3）。在AIM中最大化机理发现的可翻译性 1，我们将使用来自面板研究参与者中的原主气道上皮细胞，并将使用 参与者居住的英国伦敦收集的成分特征PM2.5。在AIM 2小组研究中，40 对于鼻液中的SPM的参与者和40名没有哮喘的参与者将进行4次测量 诱导的痰液，分别代表PM2.5进入和肺部的第一个门户。详细的个人PM2.5 源特异性PM2.5的剂量和内部剂量（生物标志物）构成SPM之前的几小时 测量将与痰液和鼻SPM浓度有关。我们预计会看到差异 分别在时间浓度概况中通过哮喘和性别。在AIM 3中，通过利用小组研究的富人 关于临床相关性健康结果的数据集，我们将研究SPM对暴露的中介作用 - 在AIMS 1和 2。全部一起，我们预计将调节SPM生物合成的分子机制与分辨率联系起来 动力学以及对PM2.5的临床功能和炎症反应。该研究将产生现实生活 数据以更好地了解SPM在解决哮喘患者中污染引起的注射中的作用 相对于非雅典和男性与女人的恋者。 1