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: 8523180
• 负责人: JO RAE WRIGHT
• 金额: $ 28.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523180
• 关键词: Allergens; Allergic; Allergic inflammation; Asthma; Bacteria; Biological Models; Cell physiology; Cells; Chronic; Developed Countries; Development; Disease; Epithelial Cells; Exposure to; Frequencies; Genetic Variation; Host Defense; Human; Immune; Immune response; Immune system; In Vitro; Incidence; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Instruction; Knockout Mice; Lead; Leukocytes; Link; Lung; Mediating; Mediator of activation protein; Modeling; Mycoplasma pneumoniae; Ovalbumin; Oxidants; Ozone; Patients; Pattern; Play; Pneumonia; Predisposition; Prevalence; Proteins; Pulmonary Surfactant-Associated Protein A; Regulation; Role; Testing; Variant; airway inflammation; cytokine; in vivo; macrophage; response; surfactant

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)持续性炎症、气道狭窄和高反应性的模式。一直 在过去的十年里，哮喘的患病率呈指数级增长，部分原因是 这归因于越来越多地暴露于包括氧化剂和感染剂的环境损害。肺宿主 对这些损伤的防御是由肺先天免疫系统介导的， 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 作为表面活性剂的一种成分，在介导肺宿主对炎症和 传染源有待检验的假设是SP-A在连接先天性 和适应性免疫反应的肺部挑战，导致或加剧哮喘， 由于等位基因变异导致SP-A或其活性缺陷导致对哮喘的易感性增强 并偏向于TH 2细胞因子反应。我们将使用一个模型系统，它结合了一种传染性的 挑战，M。用卵白蛋白致敏，研究SP-A在过敏性肺炎中的作用。 和感染性炎症。非典型细菌M.肺炎与哮喘恶化有关 并以更高的频率存在于慢性稳定型哮喘患者的气道中， 正常健康对照。我们的初步研究表明，SP-A调节免疫细胞对M。 pneumoniae感染，SP-A缺失小鼠在用M. 肺炎或模型过敏原卵清蛋白。具体目标1是定义SP-A 保护M。肺炎炎症和感染的体外和体内，并确定是否等位基因 SP-A的变体具有被废除的调节宿主应答的能力。具体目标2是评估 SP-A在调节宿主对M.卵清蛋白背景下的肺炎感染 过敏原诱导的气道反应性和肺部炎症。