Host Defense Mechanisms in Chronic Lung Disease

慢性肺病的宿主防御机制

• 批准号: 7477830
• 负责人: JO RAE WRIGHT
• 金额: $ 255.44万
• 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/7477830
• 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)： SCCOR建议的总体目标是阐明先天免疫和获得性免疫在慢性肺部疾病发病机制中的作用。SCCOR提案包括四个相互关联的研究项目，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)，其共同的潜在主题是上皮损伤、炎症、修复和纤维增殖。需要检验的中心假设是，慢性肺病的发生是宿主对常见的挑战肺部的环境侮辱做出破坏性或不适应的反应的结果。天然的和适应性的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和恢复组织完整性。虽然在宿主反应正常的情况下可以解决，但当一个关键的宿主因子失活、失调或功能失调时，外源性的侮辱就不能被遏制了。这种不适应的宿主反应会导致慢性肺部疾病。该SCCOR提案中的项目特定假设是：项目1：由肺泡和呼吸道细胞产生的表面活性蛋白SP-A和SP-D与适应性免疫系统和天然免疫系统的细胞相互作用，以协调最大限度地防御吸入性过敏原，并导致和加剧哮喘，同时将可能导致炎症、组织损伤和慢性肺部疾病的过度活跃的免疫反应降至最低。项目2：白介素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、胶原表达和弹性蛋白表达减少的气道重塑来调节哮喘患者的气道成纤维细胞功能。项目3：通过移植肺中的Toll样受体(TLRs)激活天然免疫，促进适应性同种免疫反应，导致急性排斥反应和BOS。项目4：先天性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的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部疾病的新疗法提供基础。(摘要结束) 个别项目和核心单位 项目1.表面活性蛋白在哮喘中的免疫保护作用 (Wright，Jo R.) 描述(由申请人提供)： 尽管肺表面活性物质传统上被认为是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。两种表面活性蛋白SP-A和SP-D是天然免疫蛋白家族的成员，称为集合素，与病原体结合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。在这项提议中要检验的总体假设是SP-A和SP-D。它们由肺泡和呼吸道细胞合成和分泌，与适应性免疫系统和天然免疫系统的细胞相互作用，最大限度地防御导致和加剧哮喘的吸入性过敏原，同时最大限度地减少可能导致持续性炎症、组织损伤和慢性肺部疾病的过度活跃的免疫反应。我们建议评估SP-A和SP-D在调节两种免疫细胞功能中的作用，这两种免疫细胞在哮喘发病机制中起作用：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抑制淋巴细胞增殖，调节树突状细胞产生调节性和炎性因子，SP-A基因缺失的小鼠对肺损伤和过敏性炎症的易感性增加。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抑制哮喘儿童免疫细胞由变应原诱导的淋巴细胞增殖和组胺释放，以及SP-D缺失的小鼠更容易发生过敏性炎症。提出了四个目标。目的1将确定SP-A和SP-D及其受体，包括Toll样受体(Toll Like Receptor，TLRs)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。目的研究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细胞的增殖和分化为TH1或TN2表型。目的3通过建立小鼠哮喘模型和胶原素缺失小鼠慢性变态反应性炎症模型，探讨SP-A和SP-D在炎症性肺病发病机制中的作用。目的4比较哮喘患者和正常人灌洗液中SP-A和SP-D的水平。这些研究将提供有关SP-A和SP-D在调节获得性免疫系统两个重要细胞功能中的作用的信息，并有助于我们理解SPA和SP-D在炎症性肺病中的作用。该项目结合项目2、3和4调查TLRs在慢性肺部疾病中的作用。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互动。(摘要结束)