Oxidative Stress: Antigen-Induced Allergic Inflammation

氧化应激：抗原诱导的过敏性炎症

基本信息

批准号：
7392740
负责人：
ISTVAN Steven BOLDOGH
金额：
$ 21.51万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
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/7392740
关键词：
3-nitrotyrosine 5,5&apos ,6,6&apos -tetrachloro-1,1&apos ,3,3&apos -tetraethylbenzimidazolocarbocyanine A549 Abbreviations Acetylcysteine Affect Air Algorithms Allergens Allergic Alternaria Ambrosia Ambrosia artemisiifolia Amb a I protein Anions Antigen Presentation Antigens Antimycin A Antioxidants Arts Ascorbic Acid Aspergillus Asthma Base Excision Repairs Biochemical Biological Breathing Bronchoalveolar Lavage Cell Line Cell Separation Cells Cereals Collaborations Complex Conjunctivitis Cultured Cells Data Disease Electron Transport Electron Transport Complex III Electrons Enzymes Epithelial Cells Epithelium Evaluation Studies Event Exposure to Extrinsic asthma Gene Activation Gene Expression Generations Genes Genetic Transcription Glutathione Glutathione Disulfide Glutathione Reductase Goals Hydrogen Peroxide Hydroxyl Radical Hypochlorous Acid Hypochlorous Acids IgE Immunoassay Individual Infection Infiltration Inflammation Inflammatory Injury Iodides Knock-out Knockout Mice Knowledge Laboratories Lipids Liquid substance Lung Lung Inflammation Malondialdehyde Manganese Superoxide Dismutase Measures Mediating Mediator of activation protein Membrane Membrane Potentials Messenger RNA Methods Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molds Mucins Mucous body substance Mus NAD(P)H oxidase NADH dehydrogenase (ubiquinone)NADP NADPH Oxidase NF-kappa B Nitroblue Tetrazolium Numbers Outcome Ovalbumin Oxidants Oxidation-Reduction Oxidative Stress Oxidoreductase Pathogenesis Pathway interactions Penicillium Peptides Permeability Peroxides Phase Plants Pneumonia Pollen Polymerase Chain Reaction Prevention Production Protein Overexpression Proteins Pyroglyphidae Quinacrine Reactive Oxygen Species Respiration Reverse Transcriptase Polymerase Chain Reaction Role Rotenone Services Side Signal Transduction Site Specificity Superoxide Dismutase Superoxides T-Lymphocyte Techniques Testing Therapeutic Therapeutic Uses Tissues Trees Western Blotting Wild Type Mouse Xanthine Dehydrogenase airway epithelium airway hyperresponsiveness airway inflammation alkoxyl radical allergic airway inflammation base chemokine coping cytokine dichlorofluorescin dihydroethidium eosinophil experience glucose oxidase glutathione peroxidase inhibitor/antagonist injured insight mitochondrial membrane mitochondrial permeability transition pore mouse model mutant novel particle perhydroxyl radical prevent programs research study respiratory response size

项目摘要

We provide evidence that subpollen particles contains major antigenic allergenic components of ragweed pollen grains and have robust NAD(P)H oxidase activity. Exposure of bronchial airway epithelial cells to subpollen particles changes mitochondrial permeability transition pore size, inner membrane potential and mediate sustained ROS production. Challenge of sensitized mice with these particles induce robust allergic inflammation, hyper responsiveness and mucin production. Rotenone, an inhibitor of electron flow from complex I to complex III in the mitochondria electron transport chain significantly decreased, while, co-challenge of mice with subpollen particles+ antimycin A (increase H2O2 production from inter-membrane side of complex III) augments airway inflammation and mucin production in experimental mouse model of asthma. We propose a novel "mitochondrial signal" hypothesis in which antigen presentation to T-helper 2 cells generates an "antigen-mediated signal" via specific T-cell recognition and injured mitochondria deliver a facilitating signal resulting in vigorous allergic airway inflammation. The central hypothesis of this project is that subpollen particle-initiated oxidative injury to mitochondria result in sustained increase in cellular oxidative stress level that is required for inflammatory chemokine production and vigorous antigen-driven allergic inflammation. We will test our hypothesis by examining whether sub-pollen particles induce 1) overexpression of inflammatory mediators and mucus in airway epithelium that is dependent on mitochondrial release of ROS ; 2) damage to mitochondrial membranes and respiratory complexes, which become the site for ROS generation in airway epithelial cells; and 3) mitochondrial ROS-mediated activation of NF-kappaB-dependent gene network for production of pro-inflammatory mediators in airway epithelial cells. Our goals are to elucidate the basis for therapeutic invention of allergic inflammation in sensitized individuals by use of therapeutics that increases mitochondria capacity to prevent or cope with oxidative injury or suppress ROS generation at the mitochondrial respiratory complexes.

我们提供的证据表明，亚花粉颗粒含有主要的抗原过敏成分豚草花粉粒并具有强大的 NAD(P)H 氧化酶活性。暴露支气管气道上皮细胞对亚花粉颗粒的作用改变了线粒体通透性转变孔径、内膜电位并介导持续的ROS产生。用这些颗粒刺激致敏小鼠会诱发强烈的过敏性炎症、高反应性和粘蛋白产生。鱼藤酮（线粒体电子传递链中从复合物 I 到复合物 III 的电子流抑制剂）显着减少，而用亚花粉颗粒 + 抗霉素 A 共同攻击小鼠（增加复合物 III 膜间侧的 H2O2 产生）会加剧气道炎症和哮喘实验小鼠模型中粘蛋白的产生。我们提出了一种新的“线粒体信号”假说，其中抗原呈递给 T 辅助细胞 2 细胞，通过特异性 T 细胞识别产生“抗原介导的信号”，受损的线粒体传递促进信号，导致严重的过敏性气道炎症。该项目的中心假设是，亚花粉颗粒引发的氧化损伤线粒体导致细胞氧化应激水平持续增加，这是炎症趋化因子的产生和剧烈的抗原驱动的过敏性炎症。我们将通过检查亚花粉颗粒是否诱导 1) 气道上皮中炎症介质和粘液的过度表达来检验我们的假设，这依赖于线粒体释放 ROS； 2）线粒体膜和呼吸复合体受损，这些成为气道上皮细胞中ROS生成的场所； 3) 线粒体ROS介导的NF-κB依赖性基因网络的激活，用于在气道上皮细胞中产生促炎介质。我们的目标是通过使用增加线粒体预防或应对氧化损伤或抑制线粒体呼吸复合物产生ROS的能力的疗法来阐明过敏个体过敏性炎症治疗发明的基础。