Immunoprotective Effects of Surfactant Proteins in Asthma

表面活性蛋白在哮喘中的免疫保护作用

• 批准号: 7231533
• 负责人: JO RAE WRIGHT
• 金额: $ 29.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-19 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231533
• 关键词: T lymphocyte; airborne allergen; antigens; asthma; chronic obstructive pulmonary disease; clinical research; dendritic cells; human subject; immune response; immune system; immunity; inflammation; laboratory mouse; leukocyte activation /transformation; lung; proteins; pulmonary surfactants; role; surfactant

Although pulmonary surfactant has been traditionally viewed as a surface tension reducing substance, recent studies demonstrate that it also functions in host defense. Two surfactant proteins, SP-A and SP-D, are members of a family of innate immune proteins known as collectins that bind pathogens and facilitate their clearance by immune cells. SP-A and SP-D also regulate a variety of immune cell functions. The overall hypothesis to be tested in this proposal is that SP-A and SP-D. which are synthesized and secreted by both alveolar and airway cells, interact with cells of both the adaptive and innate immune systems to coordinatelv maximize defense against inhaled allergens and that cause and exacerbate asthma, while minimizing an over exuberant immune response that could result in persistent inflammation, tissue damage and chronic lung disease. We propose to evaluate the roles of SP-A and SP-D in regulating functions of two immune cells that play a role in asthma pathogenesis: dendritic cells and T-lymphocytes. Preliminary studies show that SP-D enhances antigen uptake and presentation by dendritic cells, that SP-A and SP-D inhibit lymphocyte proliferation, modulate production of regulatory and inflammatory cvtokines by dendritic cells and that SP-A null mice have enhanced susceptibility to lung injury and allergic inflammation. Our hypothesis is also supported by published studies showing that SP-A and SP-D inhibit allergen-induced lymphocyte proliferation and histamine release by immune cells from asthmatic children and by studies showing that SP-D null mice are more susceptible to allergic inflammation. Four aims are proposed. Aim 1 will determine the mechanisms by which SP-A and SP-D and their receptors, including toll like receptors (TLRs), regulate dendritic cell function. Studies will be conducted in vitro with isolated cells and in vivo with mice. Aim 2 will investigate the mechanism by which SP-A and SP-D regulate lymphocyte activation and whether SP-A and SP-D directly or indirectly (via dendritic cells) affect T-cell proliferation and polarization to a TH1 or Tn2 phenotype. Aim 3 is to investigate the role of SP-A and SP-D in the pathogenesis of inflammatory lung disease using mouse models of asthma and chronic allergic inflammation in collectin null mice. Aim 4 is to compare characterize levels of SP-A and SP-D in lavage fluid from asthmatics and normals. These studies will provide information about the role of SP-A and SP-D in regulating the functions of two important cells of the adaptive immune system and contribute to our understanding of the role of SPA and SP-D inflammatory lung diseases. This project investigates the role of TLRs in chronic lung disease in conjunction with Projects 2, 3 and 4. In addition, patient samples from Project 2 will be analyzed. The project will interact with all the Cores.

尽管传统上将肺表面活性剂视为减少表面张力的物质，但 最近的研究表明，它还在宿主防御中起作用。两个表面活性剂蛋白，SP-A和SP-D， 是一个固有免疫蛋白家族的成员，称为结合病原体并促进 它们通过免疫细胞清除。 SP-A和SP-D还调节各种免疫细胞功能。这 在此提案中要检验的总体假设是SP-A和SP-D。合成和分泌的 通过牙槽和气道细胞，与适应性和先天免疫系统的细胞相互作用 坐标最大程度地防止吸入过敏原并引起哮喘，而这种情况则加重 最大程度地减少过度旺盛的免疫反应，这可能导致持续的炎症，组织损伤 和慢性肺部病。我们建议评估SP-A和SP-D在调节功能中的作用 在哮喘发病机理中起作用的两个免疫细胞：树突状细胞和T淋巴细胞。初步的 研究表明，SP-D增强了树突状细胞的抗原摄取和表现，SP-A和SP-D 抑制淋巴细胞增殖，通过树突状调节调节性和炎症性CVTOKINE的产生 细胞和SP-A NULL小鼠对肺损伤和过敏性炎症具有增强的敏感性。我们的 已发表的研究表明，SP-A和SP-D抑制过敏原诱导的，也支持假设 免疫细胞从哮喘儿童和研究 表明SP-D NULL小鼠更容易受到过敏性炎症的影响。提出了四个目标。目标1 将确定SP-A和SP-D及其受体的机制，包括Toll类似于受体 （TLR），调节树突状细胞功能。研究将在体外与分离的细胞和体内进行体外进行 老鼠。 AIM 2将研究SP-A和SP-D调节淋巴细胞激活和的机制 SP-A和SP-D是直接或间接（通过树突细胞）影响T细胞增殖和极化 TH1或TN2表型。目的3是研究SP-A和SP-D在发病机理中的作用 使用哮喘和慢性过敏性炎症的小鼠模型炎症性肺部疾病 老鼠。 AIM 4是比较哮喘患者的灌洗液中SP-A和SP-D的特征 正常。这些研究将提供有关SP-A和SP-D在调节功能中的作用的信息 自适应免疫系统的两个重要细胞，并有助于我们理解水疗中心的作用 和SP-D炎性肺部疾病。该项目调查了TLR在慢性肺病中的作用 与项目2、3和4结合使用。此外，将分析项目2的患者样本。这 项目将与所有核心互动。