A Novel mechanism for Environmentally Induced Airway Disease

描述(由申请人提供)：空气污染是多种呼吸道疾病的危险因素，在全身和肺部都与加重自身免疫有关。人类疾病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中的芳香烃(PAHs)，促进肺内Th17的分化和炎症，从而加重环境诱导的呼吸道疾病(EIAD)。我们对这个话题的兴趣源于肺移植的经验，其中一半的受者在移植后5年内发展为闭塞性细支气管炎综合征(BOS)，导致再次移植或死亡。BOS被认为是同种异体肺移植的慢性排斥反应，被认为是肺内Th17分化增加导致移植物破坏的结果，但其机制尚不清楚，加强免疫抑制在其治疗上也未获成功。支持环境在BOS中的作用的是最近的报告显示，肺移植受者暴露于更高水平的大气PM中，发生BOS的风险更大。我们的主要假设是，包括BOS在内的EIADs是肺与空气环境密切相关的结果。我们预测，空气中PM化学成分的细微差异会对该器官的正常免疫学产生重大影响。最近的研究发现，AHR在调节性T细胞(Treg)/Th17平衡中发挥核心作用，其中AHR的一些配体促进Treg分化，另一些配体促进Th17分化，这使得我们预测PM中的PAHs是暴露于PM后出现的毒物引起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细胞分化的成分。目标2：确定促进PM产生IL-17和IL-22所需的AHR信号转导步骤目的3：确定PM暴露是否增强了小鼠呼吸道炎症模型中的致病T细胞反应，并利用新的转基因小鼠来确定AHR表达的要求。这笔赠款的独特之处在于：将BOS视为EIAD的新颖性；我们能够基于我们的专业知识检查PM的特定成分及其与AHR的相互作用；我们可以使用大量的重组小鼠模型；我们能够将标准参考物质与真实世界的样本进行比较，以开发和测试PM增强呼吸道炎症的成分的特征。该项目与公共卫生的联系得到了EIAD高发病率的支持，除BOS外，EIAD还包括哮喘、肺气肿、慢性支气管炎和间质纤维化。我们预测，我们的发现将使我们预测哪些暴露最有可能加剧呼吸道疾病而产生的回避策略，成为治疗EIAD的新靶点。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显著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.