Nitrogen Dioxide in the Sensitization to Allergic Airway Disease

描述（由申请人提供）：过敏性哮喘的发病率在过去20年中稳步上升，现在代表着巨大的健康和经济负担。这种上升的原因尚不清楚，但环境污染物水平的增加，包括有毒的自由基气体，二氧化氮（NO2），与过敏和哮喘的发病率有关。此外，患有严重呼吸道病毒感染的儿童，其中NO2是内源性产生的，在以后的生活中患哮喘的风险较高。然而，NO2暴露可能促进过敏性致敏，导致过敏性气道疾病的发展的分子机制仍然未知。本提案的主题是阐明这些机制。某些内源性分子，包括从坏死细胞释放的碎片组分，可能通过Toll样受体（TLR）2或TLR 4的信号传导而具有免疫刺激性，导致涉及衔接蛋白MyD 88的细胞内信号传导和转录因子NF-κ B的活化。在肺上皮细胞中，NF-κ B调节CCL 20的表达，CCL 20促进树突状细胞（DC）向肺的募集。DC通过以抗原特异性方式刺激T辅助细胞来诱导适应性免疫应答，并且可以使它们朝向Th 2，这是赋予过敏性气道疾病致敏性所必需的步骤。该建议的中心假设是，NO2暴露通过刺激肺上皮TLR 2或TLR 4、MyD 88和NF-κ B促进对吸入抗原的致敏，从而促进树突状细胞的募集和成熟。这一假设将在三个特定的目标中进行测试，其中将在小鼠中测量过敏性致敏性和过敏性气道疾病的主要特征的产生，所述小鼠缺乏（TLR 2、TLR 4或MyD 88）或抑制（气道和/或肺泡2型上皮NF-κ B）在这些信号通路的成员中，以及在骨髓嵌合小鼠中，以区分这些分子在造血来源的细胞（DC）与结构肺细胞（上皮）中的重要性。

DESCRIPTION (provided by applicant): The incidence of allergic asthma has risen steadily over the last 20 years and now represents an enormous health and financial burden. Reasons for this rise remain unclear, but increases in ambient pollutant levels, including the toxic free radical gas, nitrogen dioxide (NO2), correlate with the incidence of allergy and asthma. Additionally, children with severe respiratory viral infections, in which NO2 is generated endogenously, are at an elevated risk of developing asthma later in life. However, the molecular mechanisms by which NO2 exposure may facilitate allergic sensitization, leading to the development of allergic airway disease remains unknown. Elucidating these mechanisms is the subject of this proposal. Certain endogenous molecules, including components of the debris released from necrotic cells, may be immunostimulatory by signaling through Toll-Like Receptor (TLR)2 or TLR4, leading to intracellular signaling involving the adaptor protein, MyD88, and activation of the transcription factor, NF-kappaB. In pulmonary epithelial cells, NF-kappaB modulates expression of CCL20, which promotes the recruitment of dendritic cells (DCs) to the lungs. DCs induce adaptive immune responses by stimulating T helper cells in an antigen- specific manner and may polarize them towards Th2, steps necessary to confer sensitization to allergic airway disease. The central hypothesis of this proposal is that NO2 exposure facilitates the sensitization to inhaled antigen through the stimulation of pulmonary epithelial TLR2 orTLR4, MyD88, and NF-kappaB, promoting dendritic cell recruitment and maturation. This hypothesis will be tested in three specific aims in which allergic sensitization and the generation of cardinal features of allergic airway disease will be measured in mice deficient (TLR2, TLR4 or MyD88) or inhibited (airway and/or alveolar type 2 epithelial NF-kappaB) in members of these signaling pathways, as well as in bone marrow chimeric mice, in order to distinguish the importance of these molecules in cells of hematopoietic origin (DCs) versus structural lung cells (epithelium).