Complement in Allergic Lung Disease

描述（由申请人提供）：本研究提案的目的是描述补体用于介导过敏性肺病发病机制的总体贡献和潜在机制。该提案的具体目标是由补体激活产物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）的中心假设驱动的。该建议的结果将有助于评估补体作为治疗哮喘的可能治疗靶点。将使用特异性补体缺乏小鼠中变应原诱导的肺过敏模型来鉴定在介导过敏性肺病发病机制中潜在重要的补体途径、激活片段和受体。将检查接受该模型的补体缺陷动物的哮喘病理学和生理学标志的衰减，包括AHR、气道粘液分泌过多、IgE水平升高和肺嗜酸性粒细胞。Th 2细胞因子（IL-4，IL-5，IL-13），已提出在哮喘中发挥关键作用，也将检查改变的表达。除了鼠实验性过敏模型之外，还将使用人T细胞以及从过敏性肺病患者中分离的其他白细胞进行研究，以检查哮喘中补体介导的细胞应答的潜在改变。为实现研究目标，提出了四个具体目标：1）在变应原诱导的肺变态反应模型中检查每种补体活化途径在引发哮喘相关反应中的重要性，2）确定补体过敏毒素受体如何与哮喘相关的反应，（C3 aR和C5 aR）影响变应原诱导的肺变态反应模型中的哮喘相关反应，3）确定第五补体成分（C5）如何影响变应原诱导的肺变态反应小鼠模型中的哮喘相关反应，和4）确定补体过敏毒素（C3 a和C5 a）在调节哮喘中T细胞介导的反应中的生物学作用。

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.