Surfactant Protein-A Regulation of Innate Immunityin Asthma

表面活性蛋白-A对哮喘先天免疫的调节

• 批准号: 8325216
• 负责人: Monica Kraft
• 金额: $ 25.45万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325216
• 关键词: Agent M; Agonist; Alleles; Allergens; Allergic inflammation; Alveolar Macrophages; Animal Disease Models; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Attenuated; Bacteria; Binding; Breathing; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cells; Chemicals; Child; Chronic; Chronic Obstructive Airway Disease; Clinical; Collectins; Data; Development; Disease; Disease susceptibility; Environmental Irritants; Epithelial Cells; Exhibits; Exposure to; Family; Fostering; Functional disorder; Genes; Genetic; Genetic Variation; Genotype; Goals; Growth; Heterogeneity; Histamine Release; Host Defense; Human; Immune; Immune response; Immune system; In Vitro; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Injury; Instruction; Knockout Mice; Laboratories; Lead; Lipids; Lung; Lung diseases; MUC5AC gene; Molecular; Mucous body substance; Mycoplasma; Mycoplasma pneumoniae; Natural Immunity; Opsonin; Organism; Oxidants; Ozone; Pathogenicity; Pattern; Positioning Attribute; Predisposition; Principal Investigator; Process; Production; Property; Proteins; Pseudomonas Infections; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Recombinants; Recruitment Activity; Regulation; Respiratory syncytial virus; Risk; Role; Secondary to; Severities; TLR2 gene; Testing; Therapeutic; Tuberculosis; Validation; Variant; Virus; allergic airway inflammation; base; cell injury; cytokine; environmental agent; induced pluripotent stem cell; lymphocyte proliferation; macrophage; member; microbial; novel; oxidation; ozone exposure; pathogen; programs; respiratory distress syndrome; response; surfactant; uptake

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.

已知的环境因素，包括非典型细菌、肺炎支原体和臭氧 这可能会加剧哮喘。对吸入性挑战的第一道防线是肺脏 先天免疫系统，包括表面活性蛋白。我们已经证明了SP-A与 TLR2激动剂肺炎支原体上的脂类和蛋白质，减弱其致病性。这条防线 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及免疫细胞释放组胺的研究SP-A缺失小鼠 表现出对细菌和病毒引起的感染和炎症的易感性，并表现出 增强了过敏性炎症。SP-A等位基因与多种肺部疾病有关，包括 与臭氧暴露相关的氧化剂损伤，以及最近与哮喘风险增加的关联。 这些数据表明，疾病易感性可能与改变宿主的SP-A变体有关 防御功能，并在环境侮辱的背景下提供减少的保护。因此，表面活性剂 蛋白质在减轻感染和炎症方面可能有多种作用。我们假设哮喘患者， SP-A的功能障碍，由于蛋白质的数量和功能缺陷，与 调节炎症的能力降低。这种功能障碍会导致过敏性炎症增加。 得了哮喘。我们认为，功能障碍的基础既是遗传的，也是结构性的。在目标1中，我们将 确定SP-A基因座的基因型别与实际表达的蛋白质的关系 用蛋白质组学方法研究正常人和哮喘患者的支气管肺泡室。在……里面 目的2.测定正常人和哮喘患者的SP-A活性及特异性SP-A 肺炎支原体识别中的等位基因变异及其对天然免疫的调节 人巨噬细胞的反应。在特定目标3中，我们将确定特定SP-A等位基因的活性 从正常人和哮喘患者分离的突变体和SP-A对免疫反应的调节作用 呼吸道上皮细胞对环境的侮辱分别为肺炎支原体和臭氧暴露。