Oxidative Stress & Inflammation in a Human PM Nasal Challenge

哮喘是一种多因素、复杂的疾病，多种环境因素会加剧哮喘的发病。 最近的流行病学研究结果表明，空气中的颗粒物与 物质(PM)暴露与哮喘发病率。然而，很少有关于人类挑战的研究 证明PM直接应用于呼吸道会导致呼吸道炎症。此外，还有 对PM可能诱导或增强人类呼吸道反应的机制知之甚少。 城市环境中的儿童哮喘中心的总体假设是：PM暴露==&GT； 氧化应激==&gt；呼吸道炎症=&gt；呼吸道症状。如果氧化应激途径被证明 在诱导呼吸道炎症中起关键作用，针对这一途径的治疗可能被证明是 对哮喘有效。在市中心，PM的暴露伴随着过敏原的暴露， 长期接触PM可降低暴露于小鼠后出现呼吸道症状的门槛 过敏原，城市环境中一种临床相关的过敏原。因此，我们假设PM暴露于 在IgE致敏的小鼠中引起炎性呼吸道反应并增强对变应原的呼吸道反应 哮喘患者。此外，我们假设这些炎症和生理效应是 与PM诱导的氧化应激有关。为了验证这些假设，我们将进行鼻腔和支气管 对PM和小鼠过敏原的挑战。具体目的是：(1)证明PM诱导氧化 使用已建立的鼻腔挑战模型进行应激和炎症呼吸道反应，(2)确定是否 预先接触PM可增强IgE致敏成人对随后过敏原挑战的鼻部反应 哮喘，以及(3)确定之前的PM暴露是否增强了对后续变应原的肺反应 在IgE致敏的成人哮喘患者中的挑战。这些研究的结果将通过以下方式影响哮喘健康 (1)为环境政策提供信息；(2)制定关于环境控制的未来建议 实践，以及(3)研究一种可以在小说发展中有针对性的机制路径 后续研究中的哮喘治疗。

Asthma is a multifactorial, complex disease, which is exacerbated by multiple environmental factors. Findings from recent epidemiologic studies have suggested an association between both airborne particulate matter (PM)exposure and asthma morbidity. However, there have been very few human challenge studies demonstrating that direct application of PM to airways leads to airways inflammation. In addition, there is little understanding of the mechanisms by which PM might induce or potentiate human airways responses. The Center for Childhood Asthma in the Urban Environment's overall hypothesis is that: PM exposure ==> oxidative stress ==> airways inflammation ==> airways symptoms. If the oxidative stress pathway proves to play a key role in induction of airways inflammation, therapies targeting this pathway may prove to be efficacious in asthma. In the inner-city, where exposure to PM occurs concomitantly with allergen exposure, chronic exposure to PM may lower the threshold for developing airways symptoms upon exposure to mouse allergen, a clinically relevant allergen in the urban environment. Therefore, we hypothesize that PM exposure causes inflammatory airways responses, and potentiates airways responses to allergen in IgE-sensitized individuals with asthma. Further, we hypothesize that these inflammatory and physiologic effects are associated with PM-induced oxidative stress. To test these hypotheses, we will conduct nasal and bronchial challenges to PM and mouse allergen. The specific aims are:(1) To demonstrate that PM induces oxidative stress and inflammatory airways responses using an established nasal challenge model, (2) To determine if prior PM exposure enhances nasal responses to subsequent allergen challenge in IgE-sensitized adults with asthma, and (3) To determine if prior PM exposure enhances pulmonary responses to subsequent allergen challenge in IgE-sensitized adults with asthma. The results from these studies will impact asthma health by (1) informing environmental policy, (2) shaping future recommendations regarding environmental control practices, and (3) examining a mechanistic pathway that can be targeted in the development of novel asthma therapies in subsequent studies.