Complement in Allergic Lung Disease

过敏性肺病的补体

• 批准号: 6772516
• 负责人: RICK A. WETSEL
• 金额: $ 32.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-10 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772516
• 关键词: T lymphocyte; allergens; anaphylatoxins; antigen antibody reaction; asthma; cellular immunity; clinical research; complement pathway; complement receptor; cytokine; diagnostic respiratory lavage; enzyme linked immunosorbent assay; human subject; immunoglobulin E; inflammation; laboratory mouse; lung disorder; pathologic process; plethysmography; respiratory airflow disorder; respiratory hypersensitivity; statistics /biometry

DESCRIPTION (provided by applicant): The objective of this research proposal is to delineate the overall contribution and potential mechanisms that complement utilizes to mediate the pathogenesis of allergic lung disease. The specific aims of this proposal are driven by the central hypothesis that complement activation products regulate key features of allergen-induced airway disease, including airway hyperresponsiveness (AHR) and acute airway inflammation. The results of this proposal will facilitate the evaluation of complement as a possible therapeutic target in the treatment of asthma. An allergen-induced model of pulmonary allergy in mice with specific complement deficiencies will be used to identify the complement pathways, activation fragments, and receptors that are potentially important in mediating the pathogenesis of allergic lung disease. The complement-deficient animals that are subjected to the model will be examined for attenuation of pathological and physiological hallmarks of asthma, including AHR, airway mucus hypersecretion, elevated IgE levels and lung eosinophils. The Th2 cytokines (IL-4, IL-5, IL-13) that have been proposed to play a pivotal role in asthma will also be examined for altered expression. In addition to the murine experimental allergic model, studies with human T-cells as well as other leukocytes isolated from patients with allergic lung disease will be used to examine potentially altered complement mediated cellular responses in asthma. Four specific aims are proposed to accomplish the research goals: 1) to examine the importance of each complement activation pathway in eliciting the asthma associated responses in an allergen-induced model of pulmonary allergy, 2) to determine how the complement anaphylatoxin receptors (C3aR and C5aR) affect the asthma associated responses in an allergen-induced model of pulmonary allergy, 3) to determine how the fifth complement component (C5) affects the asthma associated responses in an allergen-induced mouse model of pulmonary allergy, and 4) to determine the biological effects of the complement anaphylatoxins (C3a and C5a) in regulating T-cell mediated responses in asthma.

描述（由申请人提供）：该研究建议的目的是描述补充用于介导过敏性肺部发病机理的总体贡献和潜在机制。该提案的具体目的是由中心假设驱动的：补体激活产品调节过敏原诱导的气道疾病的关键特征，包括气道高反应性（AHR）和急性气道炎症。该提案的结果将有助于评估补体作为治疗哮喘的可能治疗靶标。具有特定补体缺乏症的小鼠中过敏原诱导的肺过敏模型将用于识别在介导过敏性肺部发病机理中可能重要重要的补体途径，激活片段和受体。将检查遭受模型的补体动物，以衰减哮喘的病理和生理标志，包括AHR，气道粘液过度分泌，IGE升高和肺嗜酸性粒细胞。提议在哮喘中起关键作用的Th2细胞因子（IL-4，IL-5，IL-13）也将被检查以改变表达。除了鼠实验过敏模型外，对人类T细胞以及从过敏性肺部疾病患者中分离的其他白细胞的研究将用于检查哮喘中补体介导的细胞反应的潜在改变。提出了四个具体目的来实现研究目标：1）检查每个补体激活途径在引起过敏原诱导的肺过敏模型中引起哮喘相关的反应中相关的反应的重要性，2），2）确定补体过敏毒素受体（C3AR和C5AR）如何影响FIFMIS与FIFMIS相关的反应，以确定pultham的反应性。成分（C5）影响过敏原诱导的肺过敏的小鼠模型中的哮喘相关反应，以及4），以确定补体过敏毒素（C3A和C5A）在调节哮喘中T细胞介导的反应中的生物学作用。