A Novel mechanism for Environmentally Induced Airway Disease

环境诱发气道疾病的新机制

• 批准号: 9185978
• 负责人: Joshua D Mezrich
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185978
• 关键词: ARNT gene; Address; Agonist; Air Pollution; Airborne Particulate Matter; Alleles; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Asthma; Attention; Autoimmunity; Breathing; Bronchiolitis Obliterans; Cell Differentiation process; Cell Nucleus; Cells; Cessation of life; Chemicals; Chronic; Chronic Bronchitis; Clinical; Cytochromes; Development; Disease; Effector Cell; Environment; Equilibrium; Exposure to; Fibrosis; Future; Generations; Genes; Genetic Transcription; Graft Rejection; Grant; Healthcare Systems; Heterodimerization; Immunology; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Inferior; Inflammation; Inflammatory; Interleukin-17; Lead; Lung; Lung Inflammation; Lung Transplantation; Lung diseases; Modeling; Morbidity - disease rate; Mus; Nature; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome; Particulate Matter; Pathogenesis; Pathogenicity; Pathology; Patients; Pharmacologic Substance; Play; Pollution; Population; Public Health; Publications; Pulmonary Emphysema; Recombinants; Reference Standards; Regulatory T-Lymphocyte; Reporting; Risk; Risk Factors; Role; Sampling; Signal Transduction; Solid; Syndrome; T cell differentiation; T cell response; T-Lymphocyte; Testing; Time; Transgenic Mice; Transplant Recipients; Transplantation; airway inflammation; aryl hydrocarbon receptor ligand; base; cytokine; experience; human disease; in vivo; in vivo Model; interest; interleukin-22; interstitial; lung allograft; mortality; mouse model; mutant; novel; outcome prediction; public health relevance; receptor; receptor binding; receptor expression; retransplantation; stem; toxicant

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.

描述（由申请人提供）：空中污染已被充分记录为多种气道疾病的危险因素，并且与系统和肺部的自身免疫性有关。在人类疾病中的机制和真正的重要性仍然不清楚。在这笔赠款中，我们研究了颗粒物（PM）的重要性，特别是多环 PM中的芳族碳氢化合物（PAHS），以增强肺中的Th17分化和炎症，这加剧了环境诱导的气道疾病（EIAD）。我们对这个话题的兴趣源于对肺移植的经验，其中一半的受体在移植后的5年内发展出细支气管炎闭塞性综合征（BOS），从而导致重新移植或死亡。被认为是肺同种异体移植的慢性排斥的BOS被认为是导致肺部Th17分化增加导致移植物破坏的结果，但是该机制尚不清楚，并且免疫抑制的增加尚未成功。最近的报道表明，暴露于更高水平的大气PM的肺移植受者有更大的BOS发展风险。我们的总体假设是，包括BOS在内的EIAD是肺部与空降环境的亲密关系的结果。我们预测，空降PM的化学成分的细微差异对该器官的正常免疫学有重大影响。最近的发现，AHR在调节性T细胞（TREG）/TH17平衡中起着核心作用，在该平衡中，AHR的某些配体增强了treg分化和其他增强Th17的分化导致我们预测PM中的PAHS在暴露于PM后看到有毒物质诱发的炎症。我们将探讨以下目的：目标1：确定影响T细胞分化的PM中包含的组件。 AIM 2：定义PM增强IL-17和IL-22生成所需的AHR信号转导步骤。 AIM 3：确定PM暴露是否增加了鼠气炎症模型中的致病性T细胞反应，并利用新型的转基因小鼠来识别AHR表达的需求。这笔赠款的独特功能是将BOS视为EIAD的新颖性，我们基于我们的专业知识的能力检查了PM的特定组成部分以及它们与AHR的相互作用，可以使用的众多重组鼠标模型，以及我们将标准参考材料与现实世界样品进行比较的能力，以开发和测试PM的组成部分，以增强空气障碍。除BOS外，该项目与公共卫生的联系得到了EIAD的高发病率，包括哮喘，肺气肿，慢性支气管炎和间质纤维化。我们预测，我们的发现将允许避免策略，这些策略将源于我们预测哪些暴露最有可能加重气道疾病的能力，即用于治疗EIAD的新目标。这将为医疗体系节省数十亿美元的增加，以最大程度地减少这些常见疾病的大量发病率和死亡率。