ALVEOLAR MACROPHAGES AND AIRWAY INFLAMMATION IN ASTHMA

描述（改编自申请人的抽象和具体目标）： 哮喘的特点是气道阻塞，支气管 高反应性和持续的气道炎症。 尽管 关于哮喘发病机制的资料积累相对较少， 细胞的作用是从根本上控制免疫系统， 反应，并调节炎症的发展和解决。 肺泡巨噬细胞（AM）通过以下途径促进哮喘炎症 促炎因子粒细胞-巨噬细胞的产生增加 集落刺激因子（GM-CSF）和超氧阴离子，或通过受损 白细胞介素（IL）-10的释放。 的 本申请假设，居民IL-10的释放受损， 哮喘中AM的募集导致持续的气道炎症， AM的功能性上调。 具体目标是：（1）建立 过敏性哮喘患者未受刺激的AM和单核细胞 在蛋白质和mRNA水平产生IL-10（和其他相关细胞因子）， 并比较对照组（过敏性鼻炎[非哮喘]受试者， 非过敏性哮喘患者和正常志愿者）; 2）建立 节段性抗原攻击或节段性盐水攻击对 AM和单核细胞在蛋白和mRNA水平上产生IL-10 过敏性哮喘患者在激发后的几个相关时间， 并与对照组进行比较; 3）确定 AM与重组人[rh] GM-CSF和干扰素（IFN）-g，或 针对这些因子的中和抗体对AM产生IL-10的影响;以及 4)为了确定AM暴露于抗IL-10抗体的作用， 和外源性rhIL-10，利用促炎因子的产生 与哮喘相关的指标（GM-CSF和超氧阴离子）。

DESCRIPTION (Adapted from the applicant's abstract and specific aims): Asthma is characterized by airway obstruction, bronchial hyperresponsiveness, and persistent airway inflammation. Despite the accumulated data regarding the pathogenesis of asthma, relatively little is known about the role of cells which fundamentally control the immune response, and which regulate development and resolution of inflammation. Alveolar macrophages (AM) contribute to inflammation in asthma, via enhanced production of the inflammogenic factors granulocyte-macrophage colony stimulating factor (GM- CSF), and superoxide anion, or by impaired release of the antiinflammatory factor, interleukin (IL)-10. The application hypothesizes that impaired release of IL-10 by resident and recruited AM in asthma leads to persistent airway inflammation, and functional upregulation of AM. The specific aims are: 1) to establish the capacity of unstimulated AM and monocytes of allergic asthmatics to produce IL-10 (and other relevant cytokines) at protein and mRNA levels, and to compare controls (allergic rhinitic [non-asthmatic] subjects, non-allergic asthmatics, and normal volunteers); 2) to establish the effects of segmental antigen challenge or segmental saline challenge on IL-10 production, at the protein and mRNA levels, by AM and monocytes of allergic asthmatics at several relevant times following challenge, and compare to controls; 3) to determine the functional consequences of AM to recombinant human [rh] GM-CSF and interferon (IFN)-g, or neutralizing antibodies to these factors, on AM production of IL-10; and 4) to determine the effects of exposure of AM to antibody against IL-10, and exogenous rhIL-10, using production of pro-inflammatory factors relevant to asthma (GM-CSF and superoxide anion) as indices.