A Novel mechanism for Environmentally Induced Airway Disease

描述（由申请人提供）：空气污染是多种气道疾病的危险因素，并与全身和肺部自身免疫加重有关。在人类疾病中的机制和真正的重要性仍然非常不清楚。在这项资助中，我们研究了颗粒物（PM）的重要性，特别是多环 PM中的芳烃（PAH），以增强肺中的Th 17分化和炎症，这加剧了环境诱导的气道疾病（EIAD）。我们对这一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年内发生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Th 17分化增加导致移植物破坏的结果，但其机制尚不清楚，并且增加的免疫抑制在其治疗中尚未成功。支持环境在BOS中的作用的是最近的报告显示，暴露于较高水平的大气PM的肺移植受者发生BOS的风险更大。我们的总体假设是，EIAD包括BOS是肺与空气环境密切关系的结果。我们预测，空气中PM的化学成分的细微差异对该器官的正常免疫学有显着的后果。最近的发现，AHR在调节性T细胞（Treg）/Th 17平衡中起着核心作用，其中AHR的一些配体增强Treg分化，其他配体增强Th 17分化，这使我们预测PM中的多环芳烃是暴露于PM后观察到的有毒物质诱导的炎症的原因。我们将探索以下目标：目标1：确定PM中包含的影响T细胞分化的组分。目的2：确定PM增强IL-17和IL-22产生所需的AHR信号转导步骤。目标3：在小鼠气道炎症模型中确定PM暴露是否增加致病性T细胞应答，并利用新型转基因小鼠确定AHR表达的要求。这项资助的独特之处在于将BOS视为EIAD的新奇，我们能够基于我们的专业知识来检查PM的特定成分及其与AHR的相互作用，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的世界样本进行比较以开发和测试增强气道炎症的PM成分的特征的能力。除了BOS之外，EIAD的高发病率支持了该项目与公共卫生的联系，包括哮喘、肺气肿、慢性支气管炎和间质纤维化。我们预测，我们的研究结果将允许避免策略，这将产生于我们的能力，以预测哪些暴露最有可能加重气道疾病，新的目标治疗EIAD。这将为卫生保健系统节省数十亿美元，并将这些常见疾病的发病率和死亡率降至最低。

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.