Pollution-Enhanced Allergic Inflammation & Enzymes

这项研究的目的是确定第二阶段酶在调节儿童对颗粒污染物增强的变态反应性炎症反应的严重程度中的作用。氧化应激是哮喘和鼻炎等过敏性呼吸道疾病炎症的结果。柴油机尾气颗粒物(DEP)等氧化性污染物会在呼吸道中造成额外的氧化负担，从而调节其生物效应。氧化应激的一个后果是诱导含有抗氧化反应元件(ARE)的基因，例如II相酶。这些酶具有强大的抗氧化作用，可能会抵消污染物的氧化作用。我们的中心假设是这一代人 在这些保护酶中，氧化剂污染物的促炎和促过敏作用的程度，在易感人群(如儿童和哮喘患者)中减少。因此，我们将在以下方面研究第二相酶在调节污染物反应中的作用：儿童的上呼吸道(目标1)；健康人和哮喘患者的下呼吸道(目标2)；过敏性炎症的机械动物和细胞模型(目标3)。目的#1将验证上呼吸道II相酶的表达是由氧化性污染物诱导的假说，并且在儿童和成人之间存在差异。这将通过确定鼻腔激发DEP是否会诱导关键的第二阶段的基因表达来实现 儿童和成人对DEP的反应是否不同，以及儿童对DEP增强的细胞反应是否与II期酶基因表达相关。目的#2将验证氧化性污染物诱导下呼吸道II相酶表达的假说，并在哮喘和非哮喘患者之间存在差异。这将通过将健康人和哮喘患者暴露在柴油废气中，并比较痰中II相酶基因的表达来实现。目的#3将确定第二阶段酶在调节氧化剂污染物的佐剂效应中的作用。这将通过确定诱导II相酶是否可以改善DEP在体内小鼠模型中对变态反应性炎症的影响以及通过 确定诱导II相酶是否可以抑制DEP诱导的肥大细胞组胺和IL-4的释放或上皮细胞细胞因子的产生。

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.