Surfactant Protein-A Regulation of Innate Immunityin Asthma

已知环境因子，包括非典型细菌、肺炎支原体和臭氧， 导致哮喘恶化。抵御吸入性挑战的第一道防线是肺部 先天免疫系统，包括表面活性蛋白。我们已经证明SP-A与 脂质和蛋白质对M. pneumoniae，TLR 2激动剂，减弱其致病性。这道防线 在哮喘中可能特别重要，因为研究表明SP-A抑制过敏原诱导的 哮喘患儿淋巴细胞增殖和免疫细胞释放组胺的研究SP-A基因敲除小鼠 对细菌和病毒引起的感染和炎症表现出增加的易感性， 增强过敏性炎症。SP-A等位基因与多种肺部疾病相关，包括 与臭氧暴露有关的氧化剂损伤以及最近与哮喘风险增加的相关性。 这些数据表明，疾病的易感性可能与SP-A的变异体有关， 防御功能，并在环境损害的情况下提供减少的保护。表面活性剂 蛋白质在减轻感染和炎症中可能具有多种作用。我们假设在哮喘中， 由于蛋白质的数量和功能缺陷，SP-A的功能障碍与 调节炎症的能力降低。这种功能障碍导致过敏性炎症增加 哮喘病我们认为，功能障碍的基础是遗传和结构。在目标1中，我们 确定SP-A基因座上的基因型与在细胞中表达的实际蛋白质之间的关系。 使用蛋白质组学方法对正常和哮喘个体的支气管肺泡隔室进行分析。在 目的2：检测正常人和哮喘患者血清中SP-A的活性及特异性SP-A 识别肺炎支原体的等位基因变体，以及先天免疫调节 人类巨噬细胞的反应。在具体目标3中，我们将确定特异性SP-A等位基因的活性， 从正常和哮喘受试者中分离的SP-A和SP-A的变体在调节免疫应答中的作用， 气道上皮细胞对环境损伤M.肺炎和臭氧暴露。

Environmental agents, including the atypical bacteria, Mycoplasma pneumoniae, and ozone are known to contribute to the exacerbation of asthma. A first line of defense against inhaled challenges is the pulmonary innate immune system, which includes the surfactant proteins. We have demonstrated that SP-A binds to lipids and proteins on M. pneumoniae, a TLR2 agonist, attenuating its pathogenicity. This line of defense may be particularly important in asthma, as studies have shown that SP-A inhibits allergen-induced lymphocyte proliferation and histamine release by immune cells from asthmatic children. SP-A null mice exhibit increased susceptibility to infection and inflammation caused by bacteria and viruses, and exhibit enhanced allergic inflammation. SP-A alleles have been associated with a variety of lung diseases including oxidant injury associated with ozone exposure and a recent association with increased risk for asthma. These data imply that disease susceptibility may be associated with variants of SP-A that have altered host defense functions and offer reduced protection in the setting of environmental insults. Therefore, surfactant proteins may have multiple roles in attenuating infection and inflammation. We hypothesize that in asthma, dysfunction of SP-A, due to quantitative and functional deficiencies in the protein, is associated with reduced ability to modulate inflammation. This dysfunction results in increased allergic inflammation in asthma. We propose that the basis of dysfunction is both genetic and structural. In Aim 1, we will determine the relationship between the genotypes at the SP-A loci and the actual proteins expressed in the bronchoalveolar compartments of normal and asthmatic individuals employing a proteonomics approach. In aim 2, we will determine the activity of SP-A isolated from normal and asthmatic subjects and specific SP-A allelic variants in the recognition of Mycoplasma pneumoniae, and the modulation of the innate immune response of human macrophages. In specific aim 3, we will determine the activity of specific SP-A allelic variants and SP-A isolated from normal and asthmatic subjects in modulation of the immune response by airway epithelial cells to the environmental insults M. pneumoniae and ozone exposure, respectively.