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.

尽管肺表面活性物质传统上被认为是降低表面张力的物质， 最近的研究表明，它也在宿主防御中发挥作用。两种表面活性蛋白SP-A和SP-D， 是被称为聚集素的先天免疫蛋白家族的成员，其结合病原体并促进 它们被免疫细胞清除。SP-A和SP-D还调节多种免疫细胞功能。的 本提案中要检验的总体假设是SP-A和SP-D。它们被合成和分泌 通过肺泡和气道细胞，与适应性和先天免疫系统的细胞相互作用， 协调地最大限度地防御吸入过敏原，并引起和加重哮喘， 最大限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， 和慢性肺病。我们建议评估SP-A和SP-D在调节细胞功能中的作用， 在哮喘发病机制中起作用的两种免疫细胞：树突细胞和T淋巴细胞。初步 研究表明，SP-D增强树突状细胞对抗原的摄取和呈递， 树突状细胞抑制淋巴细胞增殖、调节调节性和炎性细胞因子产生 SP-A基因敲除小鼠对肺损伤和过敏性炎症的易感性增强。我们 已发表的研究也支持这一假设，表明SP-A和SP-D抑制过敏原诱导的 哮喘儿童免疫细胞的淋巴细胞增殖和组胺释放 表明SP-D缺失小鼠更易发生过敏性炎症。提出了四个目标。要求1 将确定SP-A和SP-D及其受体，包括Toll样受体 （TLR），调节树突状细胞功能。研究将在体外用分离的细胞进行，在体内用 小鼠目的2探讨SP-A和SP-D调节淋巴细胞活化的机制， SP-A和SP-D是否直接或间接（通过树突细胞）影响T细胞增殖和极化， TH 1或Tn 2表型。目的3探讨SP-A和SP-D在原发性高血压发病中的作用 炎症性肺疾病使用哮喘和慢性过敏性炎症小鼠模型在胶原聚集素无效 小鼠目的4比较哮喘患者和对照组灌洗液中SP-A和SP-D的特征性水平， 正常人这些研究将为了解SP-A和SP-D在调节这些功能中的作用提供信息 适应性免疫系统的两个重要细胞，并有助于我们理解SPA的作用 和SP-D炎性肺病。本项目研究TLR在慢性肺部疾病中的作用 与项目2、3和4一起进行。此外，还将分析项目2的患者样本。的 项目将与所有核心进行交互。