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

• 批准号: 8325217
• 负责人: JO RAE WRIGHT
• 金额: $ 37.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325217
• 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

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.

哮喘是由失调的免疫反应引起的慢性炎症性疾病，导致缓慢 （TH2）持续的炎症，气道狭窄和反应性的模式。有 在过去的十年中，哮喘患病率的指数呈指数增长 归因于越来越多的环境损伤，包括氧化剂和感染剂。肺主持人 针对这些侮辱的防御是由肺部先天免疫系统介导的 白细胞和可溶性介质（例如表面活性剂）。表面活性剂蛋白A（SP-A），主要蛋白 表面活性剂的组成部分，在介导肺对炎症的反应和 感染者。要检验的假设是SP-A在联系先天性方面起着重要作用 以及对引起或加剧哮喘的肺挑战的适应性免疫反应， 由于等位基因变异，SP-A或其活性的缺陷导致对哮喘的敏感性增强 并偏向Th2细胞因子反应。我们将使用结合感染力的模型系统 挑战，肺炎支原体和对卵巢蛋白的过敏敏化，以研究SP-A在过敏性中的作用 和传染性炎症。非典型细菌M.肺炎与哮喘恶化有关 并且存在于患有慢性，稳定，哮喘患者的气道中 正常的健康对照。我们的初步研究表明，SP-A调节免疫细胞对M。 肺炎和Sp-a Null小鼠的炎症反应升高。 肺炎或模型过敏原，卵蛋白。特定目的1是定义SP-A的机制 防止体外和体内感染肺炎炎和感染，并确定是否等位基因 SP-A的变体具有调节主机响应的废除能力。具体目标2是评估 SP-A在卵巢蛋白的背景下调节宿主对肺炎支原体感染的反应 过敏原诱导的气道反应性和肺部炎症。