Role of Pollen Oxidase Induced ROS on Allergic Asthma

花粉氧化酶诱导的 ROS 对过敏性哮喘的作用

• 批准号: 6878403
• 负责人: SANJIV SUR
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878403
• 关键词: asthma; enzyme activity; free radical oxygen; hypersensitivity; pollen

Inhalation of pollens induces allergic inflammation and mucus production in the lungs of allergic subjects. "Allergenic" pollens have "major antigenic proteins" such as Amb a 1 in ragweed. In addition, they have many other proteins, some with enzyme activities. An important unresolved question is whether these enzyme activities within pollens influences allergic inflammation induced by the major pollen antigen. We have discovered that all tested pollens have intrinsic NADPH oxidase activity. Challenge with pollen extract induces oxidative stress in the lungs within minutes, associated with generation of GSSG (oxidized glutathione) and 4-HNE (lipid peroxide). Our central hypothesis is that GSSG and 4-HNE are generated by intrinsic pollen NADPH oxidases in the airway lining fluid independent of adaptive immunity. These molecules are perceived as a "Danger signal", leading to activation of signaling pathways such as p38 MAP kinases, and production of pro-inflammatory cytokines and chemokines that recruit inflammatory cells into the airways. These recruited pro-allergic inflammatory cells facilitate induction of Th2 phenotype in the airways by major pollen antigen. Here we propose to 1) Identify and quantify pro-inflammatory genes induced by GSSG and 4-HNE in the lungs independent of adaptive immunity, and determine the role of these genes in recruiting pro-allergic inflammatory cells; 2) Test the ability of GSSG and 4-HNE to provide a second signal that potentiates allergic airway inflammation induced by major pollen antigen in sensitized mice, and boosts allergic sensitization in naive mice; 3) Test the role of p38 MAPK isoforms in mediating induction of gene products by GSSG and 4-HNE that facilitates trafficking of pro-allergic inflammatory cells and augment mucin production in airway epithelial cells. At present, antigen presentation of major pollen antigen in allergic persons is thought to be to sole mechanism of induction of allergic inflammation. We propose that generation of GSSG and 4-HNE acts in concert with antigen presentation to augment allergic inflammation. These studies are likely to generate new therapeutic ideas for patients with allergic asthma that are based on suppression of GSSG and 4-HNE based signaling pathways in the lungs.

吸入花粉会引起过敏性炎症，并在过敏患者的肺部产生粘液。“致敏性”花粉含有“主要抗原蛋白”，如豚草中的amb1。此外，它们还含有许多其他蛋白质，其中一些具有酶活性。一个重要的尚未解决的问题是，花粉中这些酶的活性是否影响主要花粉抗原诱导的过敏性炎症。我们发现所有被测试的花粉都具有内在的NADPH氧化酶活性。花粉提取物在几分钟内诱导肺部氧化应激，与GSSG（氧化谷胱甘肽）和4-HNE（过氧化脂质）的产生有关。我们的中心假设是GSSG和4-HNE是由气道衬里液中独立于适应性免疫的内在花粉NADPH氧化酶产生的。这些分子被认为是一种“危险信号”，导致p38 MAP激酶等信号通路的激活，并产生促炎细胞因子和趋化因子，将炎症细胞招募到气道中。这些募集的促过敏炎症细胞通过主要花粉抗原促进气道中Th2表型的诱导。在此，我们建议：1)鉴定和量化肺中独立于适应性免疫的GSSG和4-HNE诱导的促炎基因，并确定这些基因在募集促过敏炎性细胞中的作用；2)测试GSSG和4-HNE提供二次信号的能力