Ozone Primes Pulmonary Innate Immunity

臭氧启动肺部先天免疫

• 批准号: 7673728
• 负责人: John W Hollingsworth
• 金额: $ 55.68万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673728
• 关键词: Accounting; Acetylcysteine; Address; Air Pollutants; Alveolar Macrophages; Alveolus; Animals; Apoptosis; Attenuated; Binding; Biological; Blocking Antibodies; Breathing; CD44 Antigens; Cardiovascular system; Cells; Chemicals; Disease; Epithelial; Epithelium; Exposure to; Genes; Health; Hospitalization; Human; Hyaluronan; Immune; Immune response; Immunity; Inflammatory; Inflammatory Response; Knock-out; Lipopolysaccharides; Lung; Mus; NADPH Oxidase; Natural Immunity; Ozone; Pathogenesis; Pathway interactions; Peptides; Phase; Production; Publishing; Reactive Oxygen Species; Reagent; Research; Research Personnel; Role; Surface; TNFRSF5 gene; Toll-like receptors; Transgenic Mice; Wild Type Mouse; Work; acetovanillone; airway epithelium; airway hyperresponsiveness; cytokine; hyaluronan synthase 1; in vivo; interest; lung injury; macrophage; mortality; ozone exposure; respiratory; response; toll-like receptor 4; trafficking

DESCRIPTION (provided by applicant) Ambient ozone is associated with increased respiratory illness, hospitalizations, and cardiovascular mortality. Because the lung is recurrently exposed to low level ozone, understanding how ozone modifies immune mechanisms is of considerable importance to human health. The investigators have recently demonstrated that ozone enhances both systemic and pulmonary innate immune response to lipopolysaccharide (LPS) including cytokine production, lung injury, and airway hyper-responsiveness. In addition, ozone exposure enhances subsequent LPS-induced inflammatory cell apoptosis, lowering the concentration of inflammatory cells in the alveoli. The investigators have discovered that the mechanism of ozone-priming of innate pulmonary immunity, in part, involves enhanced surface expression of toll-like receptor 4 (tlr4) on alveolar macrophages, which amplifies the biological response to inhaled LPS. The investigators now have evidence that ozone-induced release of short-fragment hyaluronan contributes to the innate immune response, and published work supports the role of NF-?B in both the response to ozone and trafficking of toll-like receptors. It is also clear that ozone inhalation is associated with the formation of reactive oxygen species (ROS), and the investigators observe that activation of NF-?B in the lung after ozone is facilitated by NADPH oxidase (NOX). However, it remains unknown whether either NOX or ROS regulate surface expression of toll-like receptor 4 and the role of surface recognition of hyaluronan in ozone priming innate immunity remain unexplored. Mechanistic understanding of the pathways that regulate trafficking of toll-like receptor 4 after exposure to this common air pollutant is of considerable interest in the pathogenesis of environmental airways disease. Thus, the overall hypothesis of this proposal is that ambient ozone modulates pulmonary innate immunity through enhanced trafficking of tlr4 to the surface of alveolar macrophages resulting in an enhanced functional response to lipopolysaccharide. Furthermore, ozone-induced trafficking of tlr4 is the result of proteolytic release of short-fragment hyaluronan, leading to NF-?B activation and amplification of the airway inflammatory response in a manner dependent on NOX2 and ROS-production. The investigators will address this hypothesis through the following Specific Aims. Specific Aim 1: Determine whether release of soluble hyaluronan contributes to ozone-dependent priming of LPS response in the lung and macrophages. Specific Aim 2: Determine the role of NF-?B activation in ozone priming of pulmonary innate immunity in lung macrophages. Specific Aim 3: Determine the role of NOX2 in regulating tlr4-dependent responses in macrophages after exposure to ozone.

描述（由申请人提供） 环境臭氧与增加的呼吸道疾病，住院和心血管死亡率有关。由于肺反复暴露于低水平的臭氧，因此了解臭氧如何修饰免疫机制对人类健康至关重要。研究人员最近表明，臭氧增强了对脂多糖（LPS）（包括细胞因子产生，肺损伤和气道高反应性）的全身和肺先天性免疫反应。另外，臭氧暴露增强了随后的LPS诱导的炎症细胞凋亡，从而降低了肺泡中炎症细胞的浓度。研究人员发现，先天性肺免疫的臭氧蛋白质的机制部分涉及在肺泡巨噬细胞上的Toll样受体4（TLR4）的表面表达增强，这扩大了对吸入LPS的生物学反应。研究人员现在有证据表明，臭氧引起的短片透明透明质酸的释放有助于先天免疫反应，并且发表的工作支持NF-？B在对臭氧反应和类似收费受体的贩运方面的作用。同样很明显，臭氧吸入与活性氧（ROS）的形成有关，研究人员观察到，NADPH氧化酶（NOX）促进臭氧后Nf- b的激活。但是，尚不清楚NOX或ROS是否调节了Toll样受体4的表面表达以及透明质酸在臭氧启动先天免疫中的表面识别的作用仍未得到探索。暴露于这种常见空气污染物后，对调节Toll样受体4运输的途径的机理理解对环境气道疾病的发病机理具有相当大的兴趣。因此，该提案的总体假设是环境臭氧通过增强TLR4向肺泡巨噬细胞表面的运输来调节肺先天免疫，从而增强对脂多糖的功能反应。此外，臭氧引起的TLR4的运输是短裂片透明质酸的蛋白水解释放的结果，导致NF-？B激活并以依赖于NOX2和ROS产生的方式扩增气道炎症反应。研究人员将通过以下特定目的解决这一假设。具体目标1：确定可溶性透明质酸的释放是否有助于肺和巨噬细胞中LPS反应的臭氧依赖性启动。具体目标2：确定NF-？B激活在肺巨噬细胞中肺先天免疫的臭氧启动中的作用。特定目标3：确定暴露于臭氧后巨噬细胞中TLR4依赖性反应中NOX2在调节TLR4依赖性反应中的作用。