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: 7392739
• 负责人: SANJIV SUR
• 金额: $ 21.81万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392739
• 关键词: 4 hydroxynonenal; A549; Acetaldehyde; Acetylcysteine; Allergens; Allergic; Allergic rhinitis; Ambrosia; Amplifiers; Animals; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Appendix; Arabs; Ascorbic Acid; Asthma; B-Lymphocytes; Biochemical; Biological; Biological Models; Bovine Serum Albumin; Breathing; Bronchoalveolar Lavage; Calcium; Cell Line; Cells; Chloride Channels; Complex; Cytokine Gene; Data; Dendritic Cells; Dependovirus; Dominant-Negative Mutation; Dose; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Event; Extrinsic asthma; Figs - dietary; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Flowers; Generations; Genes; Genetic Materials; Glutathione; Glutathione Disulfide; Human; IL8 gene; IgE; Immune response; Immunity; Immunoassay; Immunoglobulins; Immunoprecipitation; Inbred BALB C Mice; Inflammation; Inflammatory; Interleukins; Laboratories; Life; Lipid Peroxidation; Lipid Peroxides; Lipids; Liquid substance; Literature; Localized; Lung; MAP Kinase Gene; MAPK14 gene; Macrophage Inflammatory Proteins; Major Histocompatibility Complex; Malondialdehyde; Mediating; Memory; Messenger RNA; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monocyte Chemoattractant Proteins; Mucins; Mucous body substance; Mus; NADP; NADPH Oxidase; Nitroblue Tetrazolium; Ovalbumin; Oxidases; Oxidative Stress; Pathway interactions; Patients; Persons; Phase; Phenotype; Pollen; Production; Property; Protein Isoforms; Protein Overexpression; Proteins; Reaction; Reactive Oxygen Species; Recruitment Activity; Regulation; Research Personnel; Role; SCID Mice; Severe Combined Immunodeficiency; Signal Pathway; Signal Transduction; Specificity; Stress; Superoxides; System; T-Lymphocyte; Testing; Th2 Cells; Thinking; Tyrosine Phosphorylation; Western Blotting; adduct; airway epithelium; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; antigen processing; base; chemokine; cytokine; design; diphenyleneiodonium; enzyme activity; eosinophil; glutathione peroxidase; human MAPK14 protein; human subject; mRNA Expression; mitogen-activated protein kinase p38; mouse model; neutralizing antibody; neutrophil; novel; novel therapeutics; programs; research study; response; tissue culture; trafficking

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，并在过敏性受试者的肺部产生粘液。“致敏性”花粉具有“主要抗原蛋白”，如豚草中的Amb a 1。此外，它们还有许多其他蛋白质，其中一些具有酶活性。一个重要的未解决的问题是，这些酶的活动是否在花粉影响过敏性炎症引起的主要花粉抗原。我们已经发现，所有测试的花粉具有内在的NADPH氧化酶活性。用花粉提取物激发在几分钟内诱导肺中的氧化应激，与GSSG（氧化型谷胱甘肽）和4-HNE（脂质过氧化物）的产生相关。我们的中心假设是GSSG和4-HNE是由气道衬里液中的内源性花粉NADPH氧化酶产生的，不依赖于适应性免疫。这些分子被认为是“危险信号”，导致信号传导途径如p38 MAP激酶的激活，并产生促炎细胞因子和趋化因子，将炎性细胞募集到气道中。这些募集的促变应性炎性细胞通过主要花粉抗原促进气道中Th 2表型的诱导。本研究拟1）鉴定和定量GSSG和4-HNE在肺中不依赖于适应性免疫诱导的促炎基因，并确定这些基因在招募促过敏性炎症细胞中的作用; 2）检测GSSG和4-HNE提供第二信号的能力， 其在致敏小鼠中增强由主要花粉抗原诱导的变应性气道炎症，并在幼稚小鼠中增强变应性致敏; 3）测试p38 MAPK同种型在介导GSSG和4-HNE诱导基因产物中的作用，所述基因产物促进促变应性炎症细胞的运输并增加气道上皮细胞中的粘蛋白产生。目前认为，花粉主要抗原在过敏性人群中的抗原提呈是诱发过敏性炎症的唯一机制。我们认为GSSG和4-HNE的产生与抗原呈递一致，从而增加过敏性炎症。这些研究可能会为过敏性哮喘患者产生新的治疗思路， 抑制肺中基于GSSG和4-HNE的信号传导途径。