SP-A Regulation of Host Response in Asthma and Allergic Inflammation

SP-A 调节哮喘和过敏性炎症中的宿主反应

基本信息

批准号：
8381500
负责人：
JO RAE WRIGHT
金额：
$ 30.93万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8381500
关键词：
Affinity Allergens Allergic Allergic inflammation Antigens Asthma Attenuated Bacteria Binding Biological Models Cell physiology Cells Chronic Clinical Cytokine Activation Data Dendritic Cells Developed Countries Development Disease Epithelial Cells Exposure to Frequencies Genetic Variation Growth Host Defense Human Immune Immune response Immune system In Vitro Incidence Infection Infectious Agent Inflammation Inflammatory Inflammatory Response Instruction Irrigation Knockout Mice Laboratories Lead Leukocytes Link Lung Lung Inflammation Lung diseases Mediating Mediator of activation protein Microbe Modeling Mus Mycoplasma Mycoplasma pneumoniae Mycoplasma pulmonis Natural Immunity Outcome Ovalbumin Oxidants Ozone Patients Pattern Play Pneumonia Predisposition Prevalence Proteins Pulmonary Surfactant-Associated Protein A Regulation Reporting Role T-Lymphocyte Testing Time Variant Viral Virus Wild Type Mouse adaptive immunity airway inflammation base cytokine in vivo macrophage respiratory response surfactant translational study uptake

项目摘要

Asthma is a chronic inflammatory disorder caused by a dysregulated immune response that results in a Thelper (TH2) pattern of persistent inflammation, airway narrowing, and hyperresponsiveness. There has been an exponential increase in the prevalence of asthma over the past decade that has been partly attributed to growing exposure to environmental insults including oxidant and infectious agents. Lung host defense against these insults is mediated by the pulmonary innate immune system which involves leukocytes and soluble mediators such as surfactant. Surfactant protein A (SP-A), the major protein constituent of surfactant, has multifunctional roles in mediating the lung host response to inflammatory and infectious agents. The hypothesis to be tested is that SP-A plays an important role in linking innate and adaptive immune responses to pulmonary challenges that cause or exacerbate asthma and that deficiencies in SP-A or its activity due to allelic variation lead to enhanced susceptibility to asthma and skewing toward a TH2 cytokine response. We will use a model system that combines an infectious challenge, M. pneumoniae, and allergic sensitization with ovalbumin to investigate the role of SP-A in allergic and infectious inflammation. The atypical bacteria M. pneumoniae has been linked to asthma exacerbation and is present in the airways of patients with chronic, stable, asthma at a greater frequency compared to normal healthy controls. Our preliminary studies show that SP-A regulates immune cell responses to M. pneumoniae and that SP-A null mice have elevated inflammatory responses when challenged with either M. pneumoniae or the model allergen, ovalbumin. Specific Aim 1 is to define the mechanism by which SP-A protects against M. pneumoniae inflammation and infection in vitro and in vivo and to determine if allelic variants of SP-A have an abrogated ability to modulate the host response. Specific Aim 2 is to evaluate the role of SP-A in modulating the host response to M. pneumoniae infection in the context of ovalbumin allergen-induced airway reactivity and pulmonary inflammation.

哮喘是一种慢性炎症性疾病，由免疫反应失调引起，导致治疗失败 (TH2) 持续炎症、气道狭窄和高反应性的模式。有过去十年中哮喘患病率呈指数级增长，部分原因是归因于越来越多地暴露于环境损害，包括氧化剂和传染性病原体。肺主机对这些侮辱的防御是由肺部先天免疫系统介导的，该系统涉及白细胞和可溶性介质如表面活性剂。表面活性剂蛋白 A (SP-A)，主要蛋白质表面活性剂的成分，在介导肺宿主对炎症和炎症的反应中具有多功能作用传染源。待检验的假设是 SP-A 在连接先天性方面发挥着重要作用。以及对引起或加剧哮喘的肺部挑战的适应性免疫反应由于等位基因变异导致 SP-A 或其活性缺陷导致哮喘易感性增加并偏向 TH2 细胞因子反应。我们将使用一个模型系统，该系统结合了传染性攻击、肺炎支原体和卵白蛋白过敏致敏，以研究 SP-A 在过敏中的作用和感染性炎症。非典型细菌肺炎支原体与哮喘恶化有关与慢性、稳定型哮喘患者相比，其气道中存在的频率更高正常健康对照。我们的初步研究表明 SP-A 调节免疫细胞对支原体的反应。肺炎支原体和 SP-A 缺失小鼠在受到肺炎支原体攻击时炎症反应升高。肺炎链球菌或模型过敏原卵清蛋白。具体目标 1 是定义 SP-A 的机制在体外和体内预防肺炎支原体炎症和感染，并确定是否等位基因 SP-A 的变体丧失了调节宿主反应的能力。具体目标 2 是评估 SP-A 在卵清蛋白调节宿主对肺炎支原体感染反应中的作用过敏原引起的气道反应性和肺部炎症。