Oxidative stress in asthma initiation

哮喘发作时的氧化应激

基本信息

批准号：
7865835
负责人：
SANJIV SUR
金额：
$ 17.9万
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：
2004
资助国家：
美国
起止时间：
2004-04-15 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7865835
关键词：
4 hydroxynonenal Acetaldehyde Acetylcysteine Adenine Allergens Allergic Allergic inflammation Allergic rhinitis Ambrosia Anabolism Antibody Formation Antigen Presentation Antigen-Presenting Cells Antigens Antioxidants Arabs Ascorbic Acid Asthma Biochemical Biological Bovine Serum Albumin Breathing Bronchoalveolar Lavage CCL7 gene Calcium Cell Wall Cell membrane Cells Cereals Chloride Channels Chloroplasts Chronic Obstructive Airway Disease Coin Complex Country Crude Extracts DNA Dendritic Cells Dependovirus Dinucleoside Phosphates Dominant-Negative Mutation Energy Metabolism Enzymes Epithelial Cells Epitopes Extrinsic asthma Fertilization Figs - dietary Flavin Mononucleotide Flavin-Adenine Dinucleotide Flavoproteins Flowers Future Generations Genes Genetic Materials Germination Glutathione Disulfide Goals Health Human IgE Immune response Immune system Inflammation Inflammatory Inflammatory Response Interleukin-10 Interleukin-12 Interleukin-18 Interleukins Kinetics Laboratories Leishmania LACK antigen Lignin Lipid Peroxidation Liquid substance Literature Lung Lung Inflammation MHC Class II Genes Macrophage Inflammatory Proteins Major Histocompatibility Complex Malondialdehyde Mediating Mitochondria Modeling Molds Molecular Monocyte Chemoattractant Proteins Mucins Mucous body substance Mus NADH NADP NADPH Oxidase Nitroblue Tetrazolium Nose Organelles Ovalbumin Oxidases Oxidative Stress Oxidative Stress Induction Parasites Patients Peptides Phase Phenotype Phosphorylation Phosphotransferases Physiological Plants Play Poaceae Pollen Prevention Process Production Property Protein Isoforms Proteins Reactive Oxygen Species Recruitment Activity Reporting Research Design Research Personnel Respiratory Burst Role Seeds Set protein Severe Combined Immunodeficiency Signal Transduction Specificity Stress Superoxide Dismutase Superoxides Symptoms T-Cell Receptor T-Lymphocyte Testing Th2 Cells Therapeutic Tocopherols Trees Up-Regulation adaptive immunity airway epithelium airway hyperresponsiveness airway inflammation allergic airway inflammation chemokine design diphenyleneiodonium eosinophilic inflammation human disease immunoregulation inhibitor/antagonist mitogen-activated protein kinase p38 mouse model novel novel therapeutic intervention overexpression pathogen peroxisome protein complex trafficking weed pollen

项目摘要

DESCRIPTION (provided by applicant): Asthma is a major health problem in this country. Intrapulmonary allergen challenge in asthma induces a "late phase asthma phenotype," consisting of airway hyperresponsiveness (AHR), airway mucus production, and Th2 eosinophilic inflammation. A large body of literature has dissected out how peptides and epitopes of pollen-derived antigenic proteins interact with critical components of the adaptive immune system namely Class II MHC on antigen presenting cells, and T-cell receptor on Th2 cells, to induce late phase asthma phenotype. However, it has never been shown that pollens contain a second set of protein(s) with unique biochemical properties that vigorously augments late phase asthma phenotype. Ragweed pollens are known to induce allergic rhinitis and asthma in humans. We discovered that ragweed extract (RW) and many environmental pollen extracts contain potent pro-oxidant activity. Using RW as a prototypic pro-oxidant allergen, we demonstrated that this activity was due to a protein complex consisting of several distinct Pro-Oxidant Proteins (POP) tightly associated with Amb A1 (antigen E), the major antigenic component of RW. We coined a term" Pro-Oxidant Protein and Antigen Complex, (POPAC)" to describe this POP + antigen protein complex. Purified Arab A1, unlike whole RW or Amb A1 complexed in POPAC, did not possess pro-oxidant activity. Consistent with this difference in pro-oxidant activity, intrapulmonary challenge of sensitized mice with POPAC, but not Amb A1, potently induced allergic inflammation. We propose that RW (and many other pollen and mold allergens) contains POPAC, a protein complex of at least two physically associated components, the well-known antigenic component, and a novel POP. The overarching goal of this proposal is to determine the mechanism by which POP vigorously augments the late phase asthma phenotype induced by the antigenic component of POPAC. In this proposal, we will test the hypotheses that POPAC-induced immediate oxidative burst is independent of allergic sensitization and adaptive immunity (specific aim 1), and that pro-oxidant proteins augment allergic sensitization and antigen-induced late phase AHR, mucin production and Th2 allergic inflammation in mice (specific aim 2), pro-oxidant activity of RW augments immediate ROS production and late phase symptoms, mucus production and Th2 allergic inflammation in atopic patients (specific aim 3). These studies are designed to elucidate a novel paradigm of late phase asthma phenotype that is initiated by pro-oxidant protein complex (POPAC) present in many environmental pollen and mold allergens. Future studies of POPAC may identify novel therapeutic approaches in asthma.

描述（由申请人提供）：哮喘是该国的主要健康问题。哮喘中肺内过敏原挑战会引起“晚期哮喘表型”，包括气道高反应性（AHR），气道粘液产生和Th2嗜酸性粒细胞炎症。大量文献已经阐明了花粉衍生的抗原蛋白的肽和表位如何与自适应免疫系统的关键成分相互作用，即在抗原存在的细胞上II类MHC和Th2细胞上的T细胞受体，以诱导晚期哮喘表型。然而，从未证明花粉包含第二组蛋白质，具有独特的生化特性，可剧烈增强后期哮喘表型。已知Ragweed花粉会在人类中诱导过敏性鼻炎和哮喘。我们发现Ragweed提取物（RW）和许多环境花粉提取物都包含有效的促氧化活性。使用RW作为原型促氧化过敏原，我们证明了该活性是由于蛋白质复合物由与Amb A1（抗原E）紧密相关的几种不同的促氧化剂蛋白（POP）组成，RW是RW的主要抗原成分。我们创造了一个术语“促氧化剂蛋白和抗原复合物（POPAC）”来描述这种POP +抗原蛋白复合物。纯化的阿拉伯A1与在POPAC中复合的整个RW或AMB A1不同，没有促氧化活性。与促氧化活性的这种差异，对POPAC敏化小鼠的肺内挑战，而不是AMB A1的肺内挑战，可有效诱导过敏性炎症。我们建议RW（以及许多其他花粉和霉菌过敏原）包含POPAC，一种蛋白质复合物，具有至少两个物理相关的成分，即众所周知的抗原成分和一种新颖的POP。该提案的总体目标是确定POP剧烈增强POPAC抗原成分引起的晚期哮喘表型的机制。 In this proposal, we will test the hypotheses that POPAC-induced immediate oxidative burst is independent of allergic sensitization and adaptive immunity (specific aim 1), and that pro-oxidant proteins augment allergic sensitization and antigen-induced late phase AHR, mucin production and Th2 allergic inflammation in mice (specific aim 2), pro-oxidant activity of RW augments immediate ROS production and late phase特应患者的症状，粘液产生和Th2过敏性炎症（特定目标3）。这些研究旨在阐明一种晚期哮喘表型的新型范式，该型是由许多环境花粉和霉菌过敏原中存在的促氧化蛋白复合物（POPAC）引发的。对POPAC的未来研究可能会鉴定哮喘中新型的治疗方法。