Oxidative Stress & Inflammation in a Human PM Nasal Challenge

氧化应激

• 批准号: 8294886
• 负责人: Elizabeth C. Matsui
• 金额: $ 41.04万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294886
• 关键词: Adult; Affect; Airborne Particulate Matter; Allergens; Asthma; Child; Childhood Asthma; Chronic; Complex; Development; Disadvantaged; Disease; Environment; Environmental Policy; Environmental Risk Factor; Epidemiologic Studies; Exposure to; Future; Health; Human; IgE; Individual; Inflammation; Inflammatory; Life; Lung; Minority; Modeling; Morbidity - disease rate; Mus; Nose; Oxidative Stress; Oxidative Stress Pathway; Particulate Matter; Pathway interactions; Physiological; Play; Recommendation; Respiratory physiology; Shapes; Symptoms; Testing; Vulnerable Populations; airway inflammation; clinically relevant; direct application; inner city; novel; pollutant; response; socioeconomics; urban area; young adult

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.

哮喘是一种多因素，复杂的疾病，受到多种环境因素的加剧。 最近流行病学研究的发现表明，这两个空气寄生物之间存在关联 物质（PM）暴露和哮喘发病率。但是，人类挑战研究很少 证明PM直接应用于航空公司会导致气道炎症。此外，还有 对PM可能诱导或增强人类气道反应的机制几乎没有理解。 城市环境总体假设中童年哮喘的中心是：PM暴露==> 氧化应激==>气道炎症==>气道症状。如果氧化应激途径被证明为 在诱导气道炎症中起关键作用，针对该途径的疗法可能被证明是 有效的哮喘。在内部城市中，暴露于PM与过敏原暴露同时发生的城市中， 长期暴露于PM可能会降低暴露于小鼠时出现气道症状的阈值 过敏原，在城市环境中与临床相关的过敏原。因此，我们假设PM暴露 引起炎症性气道反应，并在IgE敏感的情况下增强对过敏原的气道响应 患有哮喘的人。此外，我们假设这些炎症和生理影响是 与PM诱导的氧化应激相关。为了检验这些假设，我们将进行鼻和支气管 PM和小鼠过敏原面临挑战。具体目的是：（1）证明PM诱导氧化 使用已建立的鼻挑战模型的压力和炎症气道反应，（2）确定是否是否 先前的PM暴露增强了对IgE敏感成年人的后续过敏原挑战的鼻反应 哮喘和（3）确定先前的PM暴露是否增强了对随后过敏原的肺反应 IgE敏感的成年人患有哮喘的挑战。这些研究的结果将影响 （1）告知环境政策，（2）塑造有关环境控制的未来建议 实践，以及（3）检查可以针对新颖的机械途径 随后的研究中的哮喘疗法。