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: 7839235
• 负责人: Matthew E Poynter
• 金额: $ 27.08万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7839235
• 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（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（其中二氧化氮是内源性产生的）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，导致变应性气道疾病发展的分子机制尚不清楚。阐明这些机制是本建议的主题。某些内源性分子，包括坏死细胞释放的碎片成分，可能通过toll样受体（TLR）2或TLR4信号传导产生免疫刺激作用，导致细胞内信号传导，包括接头蛋白MyD88和转录因子NF-kappaB的激活。在肺上皮细胞中，NF-kappaB调节CCL20的表达，从而促进树突状细胞（dc）向肺的募集。dc通过以抗原特异性的方式刺激T辅助细胞诱导适应性免疫反应，并可能使它们向Th2极化，这是过敏性气道疾病致敏的必要步骤。该建议的中心假设是，NO2暴露通过刺激肺上皮TLR2或tlr4、MyD88和NF-kappaB促进对吸入抗原的致敏，促进树突状细胞的募集和成熟。这一假设将在三个特定目标中进行验证，其中将在这些信号通路成员中缺乏（TLR2， TLR4或MyD88）或抑制（气道和/或肺泡2型上皮NF-kappaB）的小鼠以及骨髓嵌合小鼠中测量过敏性致敏和过敏性气道疾病的主要特征的产生，以区分这些分子在造血起源细胞（DCs）与结构肺细胞（上皮）中的重要性。