Pollution-Enhanced Allergic Inflammation & Enzymes

本研究的目的是确定II相酶在调节儿童对颗粒污染物增强的过敏性炎症反应严重程度中的作用。氧化应激是过敏性气道疾病如哮喘和鼻炎中炎症的结果。氧化性污染物如柴油机排气颗粒（DEP）在呼吸道中引起额外的氧化负担，从而介导其生物效应。氧化应激的结果是诱导含有抗氧化反应元件（ARE）的基因，例如II相酶。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。我们的核心假设是， 这些保护酶的活性控制氧化污染物的促炎和促过敏作用的程度，并且在易感亚群（例如儿童和哮喘患者）中降低。因此，我们将研究II相酶在调节对污染物的反应中的作用：儿童的上呼吸道（目标#1）;健康和哮喘个体的下呼吸道（目标#2）以及过敏性炎症的机械动物和细胞模型（目标#3）。目的#1将检验以下假设：上呼吸道中的II相酶表达由氧化污染物诱导，并且在儿童和成人之间存在差异。这将通过确定用DEP鼻激发是否会诱导关键II期的基因表达来实现。 上呼吸道中的酶，儿童和成人对DEP的反应是否不同，以及儿童对DEP的增强细胞反应是否与II相酶基因表达相关。目的#2将检验下呼吸道中的II相酶表达由氧化污染物诱导并且在哮喘和非哮喘受试者之间不同的假设。这将通过将健康和哮喘个体暴露于柴油机废气并比较痰中II相酶基因表达来实现。目标#3将确定第二阶段酶在调节氧化污染物的辅助作用中的作用。这将通过确定II相酶的诱导是否可以改善DEP在体内小鼠模型中对过敏性炎症的作用来实现，并通过测定II相酶的诱导是否可以改善DEP对过敏性炎症的作用来实现。 确定II相酶的诱导是否可以抑制DEP诱导的肥大细胞组胺和IL-4释放或上皮细胞的细胞因子产生。

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.