Nitrogen Dioxide in the Sensitization to Allergic Airway Disease

二氧化氮对过敏性气道疾病的敏感性

• 批准号: 7808774
• 负责人: Matthew E Poynter
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808774
• 关键词: Acute Lung Injury; Adaptor Signaling Protein; Air Pollution; Allergic; Alveolar; Antigens; Asthma; Bone Marrow; Breathing; CCL20 gene; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Child; Dendritic Cells; Development; Disease; Epithelial; Epithelial Cells; Epithelium; Exposure to; Extrinsic asthma; Figs - dietary; Free Radicals; Gases; Generations; Health; Helper-Inducer T-Lymphocyte; Hematopoietic; Hypersensitivity; ITGAX gene; Immune response; In Vitro; Incidence; Inflammation; Knockout Mice; Life; Lung; Measures; Molecular; Mus; NF-kappa B; Necrosis; Nitrogen Dioxide; Population; Process; Research; Resistance; Risk; Signal Pathway; Signal Transduction; TLR2 gene; TLR4 gene; Testing; Toll-Like Receptor 2; Toll-like receptors; Virus Diseases; Wheezing; allergic airway disease; in vivo; member; microbial; pollutant; respiratory; transcription factor

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).

描述(申请人提供)：过敏性哮喘的发病率在过去20年里稳步上升，现在是一个巨大的健康和经济负担。这一上升的原因尚不清楚，但环境污染物水平的上升，包括有毒自由基气体二氧化氮(NO2)，与过敏和哮喘的发生率相关。此外，患有严重呼吸道病毒感染的儿童，其中NO2是由内源性产生的，在以后的生活中患哮喘的风险更高。然而，暴露于NO2可促进过敏性致敏，导致过敏性呼吸道疾病发展的分子机制仍不清楚。阐明这些机制是这项提议的主题。某些内源性分子，包括从坏死细胞释放的碎片的成分，可能通过Toll样受体(TLR)2或TLR4发出信号，导致涉及适配蛋白MyD88的细胞内信号和转录因子NF-kappaB的激活，从而发挥免疫刺激作用。在肺上皮细胞中，核因子-kappaB调节CCL20的表达，从而促进树突状细胞(DC)向肺内募集。DC通过以抗原特异的方式刺激T辅助细胞来诱导适应性免疫反应，并可能使它们极化为Th2，这是使过敏性呼吸道疾病致敏的必要步骤。这一设想的中心假设是，暴露于NO2通过刺激肺上皮细胞TLR2或TLR4、MyD88和NF-kappaB，促进树突状细胞的募集和成熟，从而促进对吸入性抗原的敏化。这一假说将在三个特定目标中进行检验，其中将在这些信号通路成员中缺乏(TLR2、TLR4或MyD88)或抑制(呼吸道和/或肺泡2型上皮细胞核因子-kappaB)的小鼠以及在骨髓嵌合小鼠中测量过敏性呼吸道疾病的过敏性致敏和基本特征的产生，以便区分这些分子在造血细胞(DC)和结构肺细胞(上皮)中的重要性。