Mechanisms of Particulate Matter-Induced Allergic Asthma

颗粒物诱发过敏性哮喘的机制

• 批准号: 6960269
• 负责人: Peyton A Eggleston
• 金额: $ 10.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-07 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6960269
• 关键词: air pollution; airborne allergen; animal morbidity; asthma; complement; cytokine; disease /disorder etiology; disease /disorder model; gene environment interaction; gene expression; genetically modified animals; hypersensitivity; immune response; immunoregulation; inflammation; laboratory mouse; molecular pathology; particle; pollution related respiratory disorder; protein structure function; smoke inhalation; urban area

Alarming increases in the incidence, morbidity and mortality from allergic asthma in children have been documented in the US over the last decade. The underlying cause(s) of this increase are unknown. Recent epidemiological studies have documented a positive association between levels of urban airborne particulate matter (PM) and exacerbations of asthma, although a causal relationship has not been established. Importantly, preliminary studies conducted in the Center have provided compelling evidence that reductions in ambient airborne PM in homes of asthmatic children is associated with significant improvement in asthma morbidity. However, the exact mechanisms by which indoor PM exposure may exacerbate or induce asthma remain unknown. Our preliminary data suggest that exposure of mice to outdoor sources of PM alone in the absence of allergen exposure induces many features of the allergic response (Airway hyperresponsiveness, airway inflammation, Th2 cytokine production). Furthermore, our data suggest that the induction of airway hyperresponsiveness is mediated via the innate immune system mediator, complement factor 3 (C3). Interestingly, several components of indoor PM (i.e. allergens, outdoor source PM, tobacco smoke) have also been shown to activate the complement pathway. Thus the overall goal of this proposal is to establish a causal relationship between airborne indoor PM exposure and asthma morbidity and to determine the mechanisms by which indoor PM elicits these effects. Thus, we plan to test the hypothesis that individual components of indoor PM exposure serve to enhance adaptive immune responses to allergens by inducing the release or activation of C3. The specific aims of this proposal are: First, to determine whether exposure to airborne indoor PM collected from homes in urban Baltimore induces the onset or worsening of allergic asthma. Specifically, we will compare the biologic effects of PM collected in homes of children with mild and severe asthma stratified for the presence of smokers in the home. Secondly, to determine whether a gene-environment interaction is important in responses to indoor PM, we will determine the biological effects of indoor PM exposure in non-allergic strains of mice. Thirdly, we will determine the role of C3 in mediating airborne indoor PM-induced inflammation and/or exacerbations of allergic asthmatic symptoms by comparing these responses in C3 deficient and wildtype mice. These studies will provide insight into the immunopathogenic mechanisms involved in PM-induced exacerbation of asthma and establish a dose-relationship upon which to base air quality standards to protect the health of susceptible individuals in our society such as asthmatic children living in urban environments.

在过去的十年中，美国已经记录了儿童过敏性哮喘发病率，发病率和死亡率的令人震惊的增加。这种增加的根本原因是未知的。最近的流行病学研究表明，尽管尚未建立因果关系，但城市空气中颗粒物（PM）的水平（PM）与哮喘的恶化之间存在正相关。重要的是，在 中心提供了令人信服的证据，表明哮喘儿童家庭中环境空降PM的减少与哮喘发病率的显着改善有关。但是，室内PM暴露可能加剧或诱导哮喘的确切机制尚不清楚。我们的初步数据表明，在没有过敏原暴露的情况下，小鼠仅在PM的室外来源暴露会引起过敏反应的许多特征（气道高反应性，气道炎症，Th2细胞因子产生）。此外，我们的数据表明，气道高反应性的诱导是通过先天免疫系统介体，补体因子3（C3）介导的。有趣的是，室内PM的几个组成部分（即过敏原，室外来源PM，烟草烟雾）也已被证明可以激活补体途径。因此，该提案的总体目标是建立空气室室内PM暴露与哮喘发病率之间的因果关系，并确定室内PM引起这些影响的机制。因此，我们计划检验以下假设：室内PM暴露的各个成分通过诱导C3的释放或激活来增强对过敏原的适应性免疫反应。 该提案的具体目的是：首先，确定暴露于巴尔的摩城市房屋中的空降室内PM是否会引起过敏性哮喘的发作或恶化。具体而言，我们将比较在患有轻度和严重哮喘的儿童家庭中收集的PM的生物学作用，以在家庭中存在吸烟者。其次，为了确定基因环境相互作用在对室内PM的反应中是否重要，我们将确定室内PM暴露在非过敏性小鼠中的生物学作用。第三，我们 将通过比较C3缺乏和野生型小鼠的这些反应来确定C3在介导空气室室内PM诱导的炎症和/或加剧过敏性哮喘症状的作用。这些研究将提供有关PM引起的哮喘加剧的免疫致病机制的洞察力，并建立了剂量关系，以基于空气质量标准来保护我们社会中易感人群的健康状况 作为生活在城市环境中的哮喘儿童。