A Novel mechanism for Environmentally Induced Airway Disease

描述（由申请人提供）：空气污染已被充分证明是多种气道疾病的危险因素，并且会加剧全身和肺部的自身免疫。人类疾病的机制和真正重要性仍不清楚。在这笔拨款中，我们研究了颗粒物 (PM)，特别是多环物质的重要性 PM 中的芳香烃 (PAH) 会增强 Th17 分化和肺部炎症，从而加重环境诱发的气道疾病 (EIAD)。我们对此主题的兴趣源于肺移植的经验，其中一半的受者在移植后 5 年内出现闭塞性细支气管炎综合征 (BOS)，导致再次移植或死亡。 BOS被认为是肺同种异体移植物的慢性排斥反应，被认为是肺中Th17分化增加导致移植物破坏的结果，但其机制尚不清楚，并且增加免疫抑制对其治疗尚未成功。最近的报告显示，暴露于较高浓度大气 PM 的肺移植受者患 BOS 的风险更大，这支持了 BOS 的环境作用。我们的总体假设是，包括 BOS 在内的 EIAD 是肺部与空气环境密切关系的结果。我们预测，空气中颗粒物化学成分的细微差异对该器官的正常免疫学产生重大影响。最近发现 AHR 在调节性 T 细胞 (Treg)/Th17 平衡中发挥着核心作用，其中 AHR 的一些配体增强 Treg 分化，而其他配体则增强 Th17 分化，这使我们预测 PM 中的 PAH 是接触 PM 后出现的毒物诱导炎症的原因。我们将探索以下目标： 目标 1：确定 PM 中影响 T 细胞分化的成分。目标 2：定义 PM 增强 IL-17 和 IL-22 生成所需的 AHR 信号转导步骤。目标 3：确定 PM 暴露是否会增强小鼠气道炎症模型中的致病性 T 细胞反应，并利用新型转基因小鼠来确定 AHR 表达的要求。这项资助的独特之处在于将 BOS 视为 EIAD 的新颖性、我们基于专业知识来检查 PM 的特定成分及其与 AHR 的相互作用的能力、我们可以使用的众多重组小鼠模型，以及我们将标准参考材料与真实世界样本进行比较的能力，以开发和测试增强气道炎症的 PM 成分的特征。该项目与公共卫生的联系得到了 EIAD 的高发病率的支持，除了 BOS 之外，还包括哮喘、肺气肿、慢性支气管炎和间质纤维化。我们预测，我们的发现将允许我们预测哪些暴露最有可能加重气道疾病的能力而产生的避免策略，以及治疗 EIAD 的新目标。除了最大限度地减少这些常见疾病的发病率和死亡率之外，这还将为医疗保健系统节省数十亿美元。

DESCRIPTION (provided by applicant): Airborne pollution is well documented as a risk factor for multiple airway diseases, and is implicated in aggravating autoimmunity, both systemically and in the lung. The mechanisms and true importance in human disease remains very unclear. In this grant we investigate the importance of particulate matter (PM), and specifically polycyclic aromatic hydrocarbons (PAHs) in PM, to enhance Th17 differentiation and inflammation in the lung, which aggravates environmentally induced airway disease (EIAD). Our interest in this topic stems from experience with lung transplantation, where half of recipients develop bronchiolitis obliterans syndrome (BOS) within 5 years of transplantation, leading to re-transplantation or death. BOS, considered to be chronic rejection of lung allografts, is thought to be the consequence of increased Th17 differentiation in the lung leading to graft destruction, but the mechanism is unknown and increased immunosuppression has not been successful in its treatment. In support of an environmental role in BOS are the recent reports showing that lung transplant recipients exposed to higher levels of atmospheric PM are at greater risk for development of BOS. Our overarching hypothesis is that EIADs including BOS are the consequence of the lung's intimate relationship with the airborne environment. We predict that subtle differences in the chemical constituencies of airborne PM have significant consequences for the normal immunology of this organ. The recent finding that the AHR plays a central role in the regulatory T cell (Treg)/Th17 balance, where some ligands of the AHR enhance Treg differentiation and others enhance Th17 differentiation has led us to predict that PAHs in PM are responsible for toxicant-induced inflammation seen after exposure to PM. We will explore the following aims: Aim 1: Identify the components contained in PM that impact T-cell differentiation. Aim 2: Define the AHR signal transduction steps required for the enhancement of IL-17 and IL-22 generation by PM. Aim 3: Determine whether PM exposure augments a pathogenic T cell response in a murine airway inflammation model and utilize novel transgenic mice to identify requirements of AHR expression. The unique features of this grant are the novelty of considering BOS as an EIAD, the ability we have based on our expertise to examine specific components of PM and their interaction with the AHR, the numerous recombinant mouse models at our disposal, and our ability to compare standard reference materials to real- world samples to develop and test a signature for components of PM that enhance airway inflammation. The connections of this project to public health are supported by the high incidence of EIAD, including asthma, emphysema, chronic bronchitis, and interstitial fibrosis, in addition to BOS. We predict that our findings will allow both avoidance strategies that will arise from our ability to predict which exposures are most likely to aggravate airway disease, to novel targets for treatment of EIAD. This will save the health care system billions of dollars in additio to minimizing significant morbidity and mortality of these common diseases.