Mechanisms of Particulate Matter Induced Dendritic Cell Activation

许多研究表明，接触空气中的颗粒物与 (PM)和哮喘指标。然而，这种联系背后的机制仍然不清楚。 利用小鼠的品系，我们已经证明了暴露在真实世界的颗粒物中 在某些品系(A/J)的小鼠中诱导过敏反应，而在另一些品系(C3H/HeJ)中不诱导过敏反应。我们的预赛 研究表明，PM暴露可能通过改变树突状细胞而增加哮喘症状的易感性 (DC)表型和功能。具体地说，我们已经做出了新的观察，即首相改变了 小鼠肺内免疫原性髓系树突状细胞与耐受性浆细胞样树突状细胞的相对比例 易感的A/J小鼠。虽然AUB调节DC功能的机制尚不清楚，但我们的 初步数据提出了以下假设：环境PM通过 协同氧化剂和模式识别受体激活树突状细胞 依赖(PRRs)通路。为了验证这一假设，我们提出了以下目标：1)确定 PM诱导上皮细胞趋化因子产生和DC的分子机制 招募，我们将检验PM诱导上皮细胞趋化因子产生和DC的假设 通过氧化应激途径招募和成熟；2)确定确切的机制，通过 哪些PM在体外改变DC细胞的表型、成熟和T细胞刺激能力，我们将评估 氧化应激和模式识别受体通路(TLR和Dectin-1)对PM-1的作用 诱导的DC表型改变(DC亚群、共刺激分子表达、细胞因子 在敏感和耐药小鼠品系中使用组合 方法(即药物抑制剂、基因工程小鼠)；以及3)确定 AUB激活的DC亚群在过敏性呼吸道易感性中的作用 在小鼠品系(A/J，C3H)体内的反应，我们将检验以下假设： 氧化剂和/或模式识别受体(TLR，Dectin-1)的激活有助于改变激活 DC和随后AUB诱导的过敏性表型的发展。与 其他项目的结果，这项提案的结果将使我们更好地了解 暴露于环境颗粒物可加剧和/或诱发呼吸道炎症和 呼吸道发病率，最终目标是将信息转化为临床应用或 可用于减少儿童哮喘发病率的干预策略。

Numerous studies have shown a strong association between exposure to airborne particulate matter (PM) and indicators of asthma. However, the mechanisms underlying this association remain unknown. Utilizing murine strains of mice, we have demonstrated that exposure to real world particulate matter induces allergic responses in some strains (A/J) of mice, while not in others (C3H/HeJ). Our preliminary studies suggest that PM exposure may confer susceptibility to asthma symptoms by altering dendritic cell (DC) phenotype and function. Specifically, we have made the novel observation that PM alters the relative proportion of immunogenic myeloid DC to tolerogenic plasmacytoid DC recruited to the lungs of susceptible A/J mice. Although the mechanisms by which AUB regulates DC function are unknown, our preliminary data suggests the following hypothesis: that ambient PM induces the allergic response via activation of dendritic cells through synergistic oxidant and pattern recognition receptor- dependent (PRRs) pathways. To test this hypothesis, we propose the following aims: 1) To determine the molecular mechanisms by which PM-induces epithelial cell chemokine production and DC recruitment, we will test the hypothesis that PM induces epithelial cell chemokine production and DC recruitment and maturation via oxidative stress pathways; 2) To determine the exact mechanisms by which PM alters DC cell phenotype, maturation and T cell stimulatory ability in vitro, we will evaluate the contribution of oxidative stress and pattern recognition receptor pathways (TLRs and dectin-1) to PM- induced alterations in DC phenotype (DC subset, costimulatory molecule expression, cytokine production, stimulation of CD4+T cells) in susceptible and resistant murine strains using a combination of approaches (i.e. pharmacological inhibitors, genetically engineered mice); and 3) To determine the contribution of AUB-activated DC subsets to susceptibility to the development of allergic airway responses in murine strains (A/J, C3H) in vivo, we will test the hypothesis that genetic differences in activation of oxidant and/or pattern recognition receptors (TLRs, dectin-1) contribute to altered activation of DC and subsequent development of the AUB-induced allergic phenotype. Taken together with the results of the other projects, the results of this proposal will provide a better understanding of how exposures to environmental particulate matter may exacerbate and/or induce airway inflammation and respiratory morbidity with the ultimate goal of translation of information into clinical applications or intervention strategies that can be used to reduce the morbidity of childhood asthma.