Host Defense Mechanisms in Chronic Lung Disease

慢性肺病的宿主防御机制

• 批准号: 7679579
• 负责人: JO RAE WRIGHT
• 金额: $ 269.01万
• 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/7679579
• 关键词: Host; Defense; Mechanisms; Chronic; Lung

DESCRIPTION (provided by applicant): The overall goal of this SCCOR proposal is to elucidate the roles of innate and adaptive immunity in the pathogenesis of chronic lung disease. The SCCOR proposal consists of four interrelated research projects that are focused on two chronic lung diseases: asthma and bronchiolitis obliterans syndrome (BOS) with a common underlying theme of epithelial injury, inflammation, repair and fibroproliferation. The central hypothesis to be tested is that chronic lung disease occurs as a consequence of destructive or maladaptive host responses to common environmental insults that challenge the lung. The fundamental roles of innate and adaptive host responses are to recognize invading antigens, pathogens or altered self components with the purpose of eradicating the offending agents and restoring tissue integrity. While resolution can occur when the host response is normal, an exogenous insult cannot be contained when a critical host factor is inactivated, dysregulated, or becomes dysfunctional. Such maladaptive host responses lead to chronic lung disease. The project specific hypotheses within this SCCOR proposal are: Project 1: Surfactant proteins SP-A and SP-D, which are produced by both alveolar and airway cells, interact with cells of both the adaptive and innate immune systems to coordinately maximize defense against inhaled allergens and that cause and exacerbate asthma, while minimizing an over exuberant immune response that could result in inflammation, tissue damage and chronic lung disease. Project 2: Interleukin 13 (IL-13) modulates airway fibroblast function in human asthma via increased expression of platelet-derived growth factor (PDGF), an adaptive host response, and subsequent airway remodeling via fibroblast proliferation, collagen expression and decreased elastin expression. Project 3: Activation of innate immunity through toll like receptors (TLRs) in the transplanted lung promotes the adaptive alloimmune response leading to acute rejection and BOS. Project 4: Innate immune mechanisms regulate chronic inflammation and tissue remodeling and specifically, host hyaluronan and TLR interactions are critical components of the injury and repair response in non-infectious lung injury, BOS and chronic asthma. These studies will contribute to our understanding of normal and altered host responses on lung structure and function and will provide a basis for investigation and development of new therapies for the treatment of chronic lung diseases. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1. Immunoprotective Effects of Surfactant Proteins in Asthma (Wright, Jo R.) DESCRIPTION (provided by applicant): 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 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. (End of Abstract)

描述（由申请人提供）： 该 SCCOR 提案的总体目标是阐明先天免疫和适应性免疫在慢性肺病发病机制中的作用。 SCCOR 提案由四个相互关联的研究项目组成，重点关注两种慢性肺部疾病：哮喘和闭塞性细支气管炎综合征 (BOS)，其共同的基本主题是上皮损伤、炎症、修复和纤维增殖。待检验的中心假设是，慢性肺病的发生是由于宿主对常见环境损害对肺部的破坏性或适应不良反应造成的。先天性和适应性宿主反应的基本作用是识别入侵的抗原、病原体或改变的自身成分，目的是根除有害物质并恢复组织完整性。虽然当宿主反应正常时可以解决问题，但当关键宿主因子失活、失调或功能失调时，外源性损伤就无法得到遏制。这种适应不良的宿主反应会导致慢性肺部疾病。该 SCCOR 提案中的项目具体假设是： 项目 1：由肺泡和气道细胞产生的表面活性蛋白 SP-A 和 SP-D，与适应性和先天免疫系统的细胞相互作用，以协调最大程度地防御吸入过敏原，导致和加剧哮喘，同时最大限度地减少过度旺盛的免疫反应，这种反应可能导致炎症、组织损伤和慢性肺部疾病。项目 2：白细胞介素 13 (IL-13) 通过增加血小板衍生生长因子 (PDGF) 的表达、适应性宿主反应以及随后通过成纤维细胞增殖、胶原蛋白表达和减少弹性蛋白表达进行气道重塑来调节人类哮喘中的气道成纤维细胞功能。项目 3：通过移植肺中的 Toll 样受体 (TLR) 激活先天免疫，促进适应性同种免疫反应，导致急性排斥反应和 BOS。项目 4：先天免疫机制调节慢性炎症和组织重塑，特别是宿主透明质酸和 TLR 相互作用是非感染性肺损伤、BOS 和慢性哮喘损伤和修复反应的关键组成部分。这些研究将有助于我们了解正常和改变的宿主对肺结构和功能的反应，并将为研究和开发治疗慢性肺病的新疗法提供基础。 （摘要完） 单个项目和核心单元 项目 1. 表面活性蛋白对哮喘的免疫保护作用 （赖特，乔·R.） 描述（由申请人提供）： 尽管肺表面活性剂传统上被视为一种降低表面张力的物质，但最近的研究表明它也具有宿主防御功能。两种表面活性剂蛋白 SP-A 和 SP-D 是先天免疫蛋白家族（称为集合素）的成员，可结合病原体并促进免疫细胞清除病原体。 SP-A和SP-D还调节多种免疫细胞功能。本提案要检验的总体假设是 SP-A 和 SP-D。由肺泡和气道细胞合成和分泌，与适应性和先天免疫系统的细胞相互作用，以协调最大限度地防御引起和加剧哮喘的吸入过敏原，同时最大限度地减少可能导致持续炎症的过度旺盛的免疫反应，组织损伤和慢性肺部疾病。我们建议评估 SP-A 和 SP-D 在调节两种在哮喘发病机制中发挥作用的免疫细胞（树突状细胞和 T 淋巴细胞）功能中的作用。初步研究表明，SP-D 增强树突状细胞对抗原的摄取和呈递，SP-A 和 SP-D 抑制淋巴细胞增殖，调节树突状细胞产生调节性和炎症细胞因子，并且 SP-A 无效小鼠增强了对肺的敏感性损伤和过敏性炎症。我们的假设也得到了已发表的研究的支持，这些研究表明 SP-A 和 SP-D 抑制过敏原诱导的淋巴细胞增殖和哮喘儿童免疫细胞释放的组胺，并且研究表明 SP-D 缺失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（包括 Toll 样受体 (TLR)）调节树突状细胞功能的机制。研究将在体外用分离的细胞进行，并在体内用小鼠进行。目标 2 将研究 SP-A 和 SP-D 调节淋巴细胞活化的机制，以及 SP-A 和 SP-D 是否直接或间接（通过树突状细胞）影响 T 细胞增殖和极化为 TH1 或 Tn2 表型。目标 3 是使用哮喘小鼠模型和集合素缺失小鼠的慢性过敏性炎症模型，研究 SP-A 和 SP-D 在炎症性肺部疾病发病机制中的作用。目标 4 是比较哮喘患者和正常人灌洗液中 SP-A 和 SP-D 的特征水平。这些研究将提供有关 SP-A 和 SP-D 在调节适应性免疫系统两个重要细胞功能中的作用的信息，并有助于我们了解 SPA 和 SP-D 炎症性肺病的作用。该项目与项目 2、3 和 4 一起研究 TLR 在慢性肺病中的作用。此外，还将分析项目 2 的患者样本。该项目将与所有核心进行交互。 （摘要完）