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: 7849548
• 负责人: Amy M Pastva
• 金额: $ 11.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849548
• 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; 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）：该计划将准备艾米M。Pastva，PT，PhD，CCS，作为学术研究医学的独立临床医生-科学家，专门研究过敏性肺病。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，以解决一个重要的公共卫生问题，哮喘发病机制。肺表面活性物质生物学权威Jo Rae Wright博士和哮喘发病机制专家Monica Kraft医学博士将担任她的导师。该提案的重点是肺表面活性蛋白（SP）-A作为哮喘免疫宿主防御调节剂的作用。尽管急性感染性疾病模型显示SP-A抑制炎症并增强病原体清除，但对其在过敏性哮喘中的作用知之甚少。使用过敏性哮喘的卵清蛋白（OVA）模型，初步数据显示，与WT小鼠相比，SP-A null（SP-A-/-）小鼠具有减弱的气道高反应性（AHR），尽管其肺中的T辅助细胞（Th）2相关炎症指数增加并且效应记忆CD 4 + T细胞增加。用一氧化氮合酶（NOS）（催化一氧化氮（NO）的酶）的一般抑制剂治疗，完全消除了衰减的AHR。因此，该建议的假设是，过敏性哮喘中SP-A缺乏导致一氧化氮（NO）生物利用度增强，这降低了AHR，并导致CD 4 + T细胞活化增强，这促进了Th 2相关炎症。目的1将确定SP-A调节NO调节过敏性肺疾病AHR的机制。在假手术和OVA处理的WT和SP-A-/-小鼠中，将在有和没有NOS抑制的情况下检查NO种类的表达水平和活性。目的2探讨SP-A在NO非依赖性和依赖性调节T细胞表型和功能中的作用。CD 4 + T细胞亚群将在离体试验、同基因共培养试验和过继转移研究中进行表型和功能表征。目的3探讨SP-A替代治疗变应性肺病的疗效。连同显示哮喘中SP-A水平降低的报告，数据表明SP-A缺乏激活对过敏性损伤的免疫应答，同时保持气道通畅。揭示这一独特模式存在的机制可能会导致肺免疫生物学的新见解，并可能影响哮喘发病率和死亡率的新疗法的发展。