Pollution-Enhanced Allergic Inflammation & Enzymes

污染加剧的过敏性炎症

• 批准号: 6960277
• 负责人: FRANK D. GILLILAND
• 金额: $ 10.27万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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/6960277
• 关键词: NAD(P)H dehydrogenase; adolescence (12-20); adult human (21+); air pollution; clinical research; disease /disorder etiology; environmental exposure; enzyme induction /repression; gene environment interaction; genetic susceptibility; genetically modified animals; glutathione transferase; histamine release; human subject; inflammation; interleukin 4; laboratory mouse; mast cell; nitric oxide; ovalbumin; oxidative stress; particle; respiratory hypersensitivity

The goal of this study is to determine the role of Phase II enzymes in regulating severity of responses to particulate pollutant-enhanced allergic inflammation in children. Oxidative stress occurs as a consequence of inflammation in allergic airway diseases such as asthma and rhinitis. Oxidant pollutants such as diesel exhaust particles (DEP) cause an additional oxidative burden in the respiratory tract and thereby mediate their biological effects. A consequence of oxidative stress is the induction of genes that contain the antioxidant response element (ARE) e.g. Phase II enzymes. These enzymes have potent antioxidant effects that potentially may counteract the oxidant effects of the pollutants. Our central hypothesis is that generation of these protective enzymes govern the extent of the pro-inflammatory and pro-allergenic effects of oxidant pollutants and are reduced in susceptible sub-populations (such as children and asthmatics). Therefore, we will study the role of Phase II enzymes in regulating responses to pollutants in: children's upper airways (Aim #1); the lower airways of healthy and asthmatic individuals (Aim #2) and in mechanistic animal and cellular models of allergic inflammation (Aim #3). Aim #1 will test the hypothesis that Phase II enzyme expression in the upper airways are induced by oxidant pollutants and differ between children and adults. This will be accomplished by determining whether nasal challenge with DEP will induce gene expression of key Phase II enzyme in the upper airways, whether this expression in response to DEP differs between children and adults and whether enhanced cellular responses to DEP in children correlate with Phase II enzyme gene expression. Aim #2 will test the hypothesis that Phase II enzyme expression in the lower airways are induced by oxidant pollutants and differ between asthmatic and non-asthmatic subjects. This will be accomplished by exposing healthy and asthmatic individuals to diesel exhaust and comparing Phase II enzyme gene expression in sputum. Aim #3 will determine the role of Phase II enzymes in regulating the adjuvant effects of oxidant pollutants. This will be accomplished by determining whether induction of Phase II enzymes can ameliorate the effects of DEP on allergic inflammation in an in vivo mouse model and by determining whether induction of Phase II enzymes can inhibit DEP-induced mast cell histamine and IL-4 release or cytokine production from epithelial cells.

这项研究的目的是确定II期酶在调节儿童对颗粒污染物增强的过敏性炎症的严重程度中的作用。氧化应激是由于过敏性气道疾病（如哮喘和鼻炎）的炎症而发生的。氧化剂污染物（例如柴油排气颗粒（DEP））在呼吸道中增加氧化负担，从而介导其生物学作用。氧化应激的结果是诱导包含抗氧化剂反应元件的基因（例如） II期酶。这些酶具有有效的抗氧化作用，可能会抵消污染物的氧化作用。我们的中心假设是一代 在这些保护酶中，氧化剂污染物的促炎和促化过敏作用的程度降低了易感的亚群（例如儿童和哮喘患者）。因此，我们将研究II期酶在调节对污染物反应中的作用：儿童上呼吸道（AIM＃1）；健康和哮喘患者的较低气道（AIM＃2）以及过敏性炎症的机械动物和细胞模型（AIM＃3）。 AIM＃1将检验以下假设：上呼吸道中II期酶的表达是由氧化剂污染物诱导的，儿童和成人之间的不同。这将通过确定鼻腔攻击是否会诱导关键II期的基因表达来实现 上呼吸道中的酶，无论对DEP的响应是否在儿童和成人之间有所不同，以及儿童对DEP的增强反应是否与II期酶基因表达相关。 AIM＃2将检验以下假设：下部气道中II期酶的表达是由氧化剂污染物诱导的，并且在哮喘和非心血管受试者之间有所不同。这将通过将健康和哮喘的个体暴露于柴油排气并比较痰液中的II期酶基因表达来实现。 AIM＃3将确定II期酶在调节氧化剂污染物的辅助作用中的作用。这将通过确定诱导II期酶是否可以改善DEP对体内小鼠模型中过敏性炎症的影响以及通过 确定诱导II期酶是否可以抑制DEP诱导的肥大细胞组胺和IL-4释放或从上皮细胞中产生细胞因子。