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.

哮喘是一种慢性炎症性疾病，由免疫反应失调引起 (Th2)持续炎症、气道狭窄和高反应性。那里有 在过去的十年里，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在环境侮辱中，包括氧化剂和感染剂。肺宿主 对这些侮辱的防御是由肺固有免疫系统介导的，它涉及 白细胞和可溶性介质，如表面活性物质。主要蛋白质表面活性蛋白A(SP-A) 肺表面活性物质的组成成分，在介导肺宿主对炎症和 感染剂。有待检验的假设是，SP-A在连接先天基因的过程中发挥着重要作用 以及对引起或加重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的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，该系统结合了具有传染性的 激发、肺炎支原体和卵蛋白致敏研究SP-A在变态反应中的作用 和感染性炎症。非典型细菌肺炎支原体与哮喘加重有关 与慢性稳定期哮喘患者的呼吸道相比，其出现的频率更高 正常健康对照组。我们的初步研究表明，SP-A调节免疫细胞对M。 肺炎和SP-A基因缺失的小鼠在感染M。 肺炎或模型过敏原卵清蛋白。具体目标1是定义SP-A 体外和体内对肺炎支原体炎症和感染的保护作用及等位基因的确定 SP-A的变异体具有调节宿主反应的能力。具体目标2是评估 卵清蛋白背景下SP-A在调节宿主对肺炎支原体感染反应中的作用 过敏原诱导的呼吸道反应性和肺部炎症。