The in vivo Role of Surfactant Protein A in Allergic Lung Disease

表面活性剂蛋白 A 在过敏性肺病中的体内作用

• 批准号: 7919724
• 负责人: Amy M Pastva
• 金额: $ 5万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919724
• 关键词: A Mouse; Absenteeism; Acute; Address; Adoptive Transfer; Air; Allergens; Allergic; Antigen-Presenting Cells; Asthma; Attenuated; Biological Assay; Biological Availability; Biological Response Modifiers; Biology; Breathing; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; CD4 Positive T Lymphocytes; Cells; Cellular biology; Chronic lung disease; Coculture Techniques; Collectins; Complex; Data; Developed Countries; Developing Countries; Development; Doctor of Philosophy; Enzymes; Equilibrium; Extrinsic asthma; Family; Glutathione; Health; Host Defense; Human; Immune; Immune response; Immunobiology; Immunology; Infection; Inflammation; Inflammation Mediators; Inflammatory; Lead; Lipoprotein (a); Liquid substance; Lung; Lung diseases; Lymphocyte; Measurement; Mediating; Medicine; Mentors; Metabolism; Modeling; Morbidity - disease rate; Mus; Nitric Oxide; Nitric Oxide Synthase; Outcome; Ovalbumin; Oxidoreductase; Pathogenesis; Phagocytes; Phenotype; Physiological; Play; Production; Proteins; Public Health; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Reactive Nitrogen Species; Regulation; Reporting; Research; Research Personnel; Rodent; Role; Schools; Scientist; Severity of illness; Surface Tension; T cell regulation; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte Subsets; Training; Universities; Virus Diseases; Wild Type Mouse; Work; airway hyperresponsiveness; airway inflammation; authority; career; cytokine; eosinophil; formaldehyde dehydrogenase; in vivo; indexing; infectious disease model; inhibitor/antagonist; insight; member; memory CD4 T lymphocyte; mortality; novel; pathogen; programs; research study; surfactant; uptake

DESCRIPTION (provided by applicant): This program will prepare Amy M. Pastva, PT, PhD, CCS, for a career as an independent clinician-scientist in academic research medicine, specializing in the study of allergic lung disease. Dr. Pastva has been pursuing rigorous training in cell biology and immunology at Duke University to address an important public health issue, asthma pathogenesis. Jo Rae Wright, PhD, an authority in lung surfactant biology, and Monica Kraft, MD, an expert in asthma pathogenesis, will serve as her mentors. The proposal focuses on the role of lung surfactant protein (SP)-A as a regulator of immune host defense in asthma. Although acute infectious disease models show that SP-A inhibits inflammation and enhances pathogen clearance, relatively little is known about its role in allergic asthma. Using the ovalbumin (OVA) model of allergic asthma, preliminary data show that SP-A null (SP-A-/-) mice have attenuated airway hyperresponsiveness (AHR) despite increased T Helper (Th) 2-associated inflammatory indices and increased effector memory CD4+ T cells in their lungs compared to WT mice. Treatment with a general inhibitor of nitric oxide synthases (NOS), the enzymes that catalyze nitric oxide (NO), completely abrogated the attenuated AHR. Thus, the hypothesis of this proposal is that SP-A deficiency in allergic asthma results in enhanced nitric oxide (NO) bioavavailability, which reduces AHR, and results in enhanced CD4+ T cell activation, which promotes Th2-associated inflammation. Aim 1 will determine the mechanisms by which SP-A regulation of NO species modulates AHR in allergic lung disease. The expression levels and activity of NO species will be examined with and without NOS inhibition in sham and OVA treated WT and SP-A-/- mice. Aim 2 will determine the role of SP-A in mediating NO independent and dependent regulation of T cell phenotype and function. CD4+ T cell subsets will be phenotypically and functionally characterized in ex vivo assays, syngeneic co-culture assays, and adoptive transfer studies. Aim 3 will explore the efficacy of using SP-A replacement in allergic lung disease. Together with reports showing reductions in the levels of SP-A in asthma, data suggest that SP-A deficiency activates an immune response to an allergenic insult whilst maintaining airway patency. Uncovering the mechanisms by which this unique paradigm exists may lead to new insights in lung immunobiology and to the development of novel therapies that may influence the morbidity and mortality of asthma.

描述（由申请人提供）：该计划将准备Amy M. Pastva，PT，PhD，CCS，成为学术研究医学领域的独立临床医生，专门研究过敏性肺部疾病的职业。 Pastva博士一直在杜克大学接受严格的细胞生物学和免疫学培训，以解决重要的公共卫生问题，即哮喘发病机理。肺部表面活性剂生物学的权威和哮喘发病机理专家莫妮卡·克拉夫（Monica Kraft）的乔·雷·赖特（Jo Rae Wright）将担任她的导师。该提案的重点是肺表面活性剂蛋白（SP）-A作为哮喘中免疫宿主防御的调节剂的作用。尽管急性传染病模型表明SP-A抑制炎症并增强病原体清除率，但对其在过敏性哮喘中的作用知之甚少。使用过敏性哮喘的椭圆形（OVA）模型，初步数据表明，尽管T助手（Th）2助理（Th）2相关的炎症指标和增加肺部的效应记忆CD4+ T细胞与WtT相比，SP-A NAULL（SP-A-/ - ）小鼠尽管T助手（TH）2次抗炎指数增加了气道高反应性（AHR）。用一氧化氮合酶（NOS）的一般抑制剂（催化一氧化氮（NO）的酶完全消除了衰减的AHR的酶。因此，该提议的假设是，过敏性哮喘的SP-A缺乏会导致一氧化氮（NO）生物利用性增强，从而降低AHR，并导致CD4+ T细胞激活增强，从而促进Th2相关炎症。 AIM 1将确定NO物种调节的机制在过敏性肺部疾病中调节AHR。在假和OVA处理过的WT和SP-A - / - 小鼠中，将检查无物种的表达水平和活性。 AIM 2将确定SP-A在介导不独立和依赖的T细胞表型和功能中的作用。 CD4+ T细胞亚群将在体内测定，合成性共培养测定和收养转移研究中在表型和功能上表征。 AIM 3将探索在过敏性肺部疾病中使用SP-A替代品的功效。随着显示哮喘中SP-A水平降低的报告，数据表明，SPA缺乏激活了对过敏反应侮辱的免疫反应，同时维持气道通畅。揭示这种独特的范式存在的机制可能会导致肺免疫生物学的新见解以及可能影响哮喘发病率和死亡率的新型疗法的发展。