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.

过去十年，美国儿童过敏性哮喘的发病率、发病率和死亡率出现惊人的增长。这种增加的根本原因尚不清楚。最近的流行病学研究证明，城市空气颗粒物 (PM) 水平与哮喘恶化之间存在正相关关系，尽管因果关系尚未确定。重要的是，初步研究在 该中心提供了令人信服的证据，表明哮喘儿童家中环境空气中 PM 的减少与哮喘发病率的显着改善相关。然而，室内 PM 暴露可能加剧或诱发哮喘的确切机制仍不清楚。我们的初步数据表明，在没有接触过敏原的情况下，小鼠单独接触室外 PM 源会诱发过敏反应的许多特征（气道高反应性、气道炎症、Th2 细胞因子的产生）。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质补体因子 3 (C3) 介导的。有趣的是，室内 PM 的几种成分（即过敏原、室外源 PM、烟草烟雾）也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中的室内 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，我们计划检验这样的假设：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。 该提案的具体目标是：首先，确定接触从巴尔的摩市区家庭收集的空气中的室内 PM 是否会诱发过敏性哮喘的发作或恶化。具体来说，我们将比较在患有轻度和重度哮喘的儿童家中收集的 PM 的生物效应，并根据家中是否有吸烟者进行分层。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 暴露对非过敏性小鼠品系的生物效应。第三，我们 将通过比较 C3 缺陷小鼠和野生型小鼠的这些反应，确定 C3 在介导空气传播的室内 PM 诱导的炎症和/或过敏性哮喘症状恶化中的作用。这些研究将深入了解PM引起的哮喘恶化的免疫致病机制，并建立剂量关系，以此作为空气质量标准的基础，以保护我们社会中易感人群的健康，例如 就像生活在城市环境中的哮喘儿童一样。