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.

吸入花粉诱导过敏性受试者肺中的过敏性炎症和粘液产生。 “过敏性”花粉具有“主要的抗原蛋白”，例如Ragweed的Amb A 1。此外，它们还有许多其他蛋白质，有些具有酶活性。一个重要的未解决的问题是花粉中的这些酶活性是否影响主要花粉抗原引起的过敏性炎症。我们发现所有测试的花粉均具有内在的NADPH氧化酶活性。花粉提取物的挑战会在几分钟内引起肺部的氧化应激，这与GSSG（氧化谷胱甘肽）和4-HNE（脂质过氧化脂蛋白）的产生有关。我们的中心假设是，GSSG和4-HNE是由独立于适应性免疫的气道衬里流体中的固有花粉氧化酶产生的。这些分子被认为是“危险信号”，导致信号通路（例如p38 MAP激酶）的激活，以及促炎性细胞因子和趋化因子的产生，这些因子和趋化细胞招募炎症细胞进入气道。这些招募的促促过敏性炎症细胞促进了主要花粉抗原在气道中诱导Th2表型。在这里，我们建议1）识别和量化由GSSG和4-HNE在肺中诱导的促炎基因，独立于适应性免疫，并确定这些基因在募集促促炎性细胞中的作用； 2）测试GSSG和4-HNE提供第二个信号的能力 这增强了敏化小鼠的主要花粉抗原引起的过敏性气道炎症，并增强了幼稚小鼠的过敏反应。 3）测试p38 MAPK同工型在通过GSSG和4-HNE介导基因产物诱导的作用，从而促进促促过敏性炎症细胞的运输并增加气道上皮细胞中的粘蛋白产生。目前，过敏反应中主要花粉抗原的抗原表现被认为是诱导过敏性炎症的唯一机制。我们提出，GSSG和4-HNE的产生与抗原表现一起起作用，以增加过敏性炎症。这些研究可能会为基于过敏性哮喘的患者产生新的治疗想法 肺中GSSG和4-HNE的信号通路的抑制。