Immunoprotective Effects of Surfactant Proteins in Asthma

尽管肺表面活性物质传统上被视为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， 是天然免疫蛋白家族的成员，被称为集合素，它结合病原体并促进 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。这个 本提案中要检验的总体假设是SP-A和SP-D。它们是合成和分泌的 通过肺泡和呼吸道细胞，与适应性免疫系统和先天免疫系统的细胞相互作用 最大限度地防御吸入性过敏原并导致和加剧哮喘，而 尽量减少可能导致持续性炎症、组织损伤的过度活跃的免疫反应 和慢性肺病。我们建议评估SP-A和SP-D在调节血管内皮细胞功能中的作用。 在哮喘发病机制中发挥作用的两种免疫细胞：树突状细胞和T淋巴细胞。初步 研究表明，SP-D促进树突状细胞对抗原的摄取和提呈，SP-A和SP-D 树突状细胞抑制淋巴细胞增殖，调节调节性和炎性因子的产生 细胞和SP-A缺失的小鼠对肺损伤和过敏性炎症的易感性增加。我们的 已发表的研究表明，SP-A和SP-D抑制变应原诱导的过敏原，这一假说也得到了支持 哮喘患儿免疫细胞淋巴细胞增殖及组胺释放的研究 表明SP-D缺失的小鼠更容易发生过敏性炎症。提出了四个目标。目标1 将决定SP-A和SP-D及其受体，包括Toll样受体的机制 (TLRs)，调节树突状细胞的功能。研究将在体外用分离的细胞进行，在体内用 老鼠。目的探讨SP-A和SP-D调节淋巴细胞活化和免疫调节的机制。 SP-A和SP-D是否直接或间接(通过树突状细胞)影响T细胞的增殖和极化 TH1或Tn2表型。目的3探讨SP-A和SP-D在糖尿病发病机制中的作用。 用小鼠哮喘模型和慢性变态反应性炎症模型建立炎症性肺病 老鼠。目的4比较哮喘患者和哮喘患者灌洗液中SP-A和SP-D的特征水平 法线。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 获得性免疫系统的两个重要细胞，有助于我们理解SPA的作用 和SP-D炎症性肺病。本项目研究TLRs在慢性肺部疾病中的作用 与项目2、3和4相结合。此外，还将分析项目2的患者样本。这个 Project将与所有核心进行交互。

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.