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）： 该SCCOR建议的总体目标是阐明先天和适应性免疫在慢性肺部疾病的发病机理中的作用。 SCCOR提案由四个相互关联的研究项目组成，这些研究项目集中在两种慢性肺部疾病上：哮喘和细支气管炎闭塞综合征（BOS），其上皮损伤，炎症，修复和纤维化促进性的共同基本主题。要检验的中心假设是，由于对挑战肺部挑战的常见环境侮辱的破坏性或适应不良的宿主反应，慢性肺部疾病发生。先天和自适应宿主反应的基本作用是识别入侵的抗原，病原体或改变的自我成分，目的是消除违规药物并恢复组织完整性。虽然当宿主响应正常时可能会发生分辨率，但是当关键宿主因子失活，失调或变功能失调时，不能包含外源性损伤。这种不良适应性宿主的反应导致慢性肺部疾病。 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慢性肺部病。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，自适应宿主反应以及随后的气道通过成纤维细胞增殖，胶原蛋白表达和降低弹性蛋白的表达来调节人类哮喘中的气道成纤维细胞功能。项目3：移植后的肺中通过类似受体（TLR）激活先天免疫力，促进了适应性的同种免疫反应，导致急性排斥和BOS。项目4：先天免疫机制调节慢性炎症和组织重塑，具体来说，宿主透明质酸和TLR相互作用是非感染性肺损伤，BOS和慢性哮喘的损伤和修复反应的关键成分。这些研究将有助于我们理解正常和改变宿主对肺结构和功能的反应，并为研究和开发新疗法的治疗方法提供基础。 （抽象的结尾） 个别项目和核心单位 项目1。表面活性剂蛋白在哮喘中的免疫保护作用 （赖特，乔。） 描述（由申请人提供）： 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，它在宿主防御中也起作用。两种表面活性剂蛋白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免疫细胞清除。 SP-A和SP-D还调节各种免疫细胞功能。在此提案中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的，与适应性和先天免疫系统的细胞相互作用，以坐在坐标，从而最大程度地防御引起和加剧哮喘的吸入过敏原，同时最大程度地减少过度杂质的免疫反应，从而导致持续的炎症，这可能导致持续的炎症，组织性损害，组织性损害，lung氏病。我们建议评估SP-A和SP-D在调节两个免疫细胞功能中的作用，这些免疫细胞在哮喘发病机理中起作用：树突状细胞和T-淋巴细胞。初步研究表明，SP-D可以增强树突状细胞的抗原摄取和表现，即SP-A和SP-D抑制淋巴细胞增殖，调节树突状细胞对调节性和炎症性CVTOKINE的产生，而SP-A无小鼠具有增强肺部损伤和炎症的易感性。我们的假设也得到了公开的研究，表明SP-A和SP-D抑制过敏原诱导的淋巴细胞增殖和免疫细胞从哮喘儿童中释放的组胺释放，并且通过研究表明SP-D NULL小鼠对过敏性炎症更敏感。提出了四个目标。 AIM 1将确定SP-A和SP-D及其受体（包括受体（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和小鼠体内进行。 AIM 2将研究SP-A和SP-D调节淋巴细胞激活以及SP-A和SP-D是否直接或间接（通过树突状细胞）影响T细胞增殖和极化对TH1或TN2表型的机制。 AIM 3是使用哮喘和慢性过敏性炎症的小鼠中的小鼠研究SP-A和SP-D在炎症性肺部疾病发病机理中的作用。 AIM 4是比较哮喘和正常水平的灌洗液中SP-A和SP-D的特征。这些研究将提供有关SP-A和SP-D在调节自适应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炎性肺部疾病的作用。该项目研究了TLR在慢性肺部疾病中的作用与项目2、3和4。此外，还将分析项目2的患者样本。该项目将与所有核心互动。 （抽象的结尾）