Surfactant Protein A Modulates Airway Response to Ozone in Human Asthma

表面活性剂蛋白 A 调节人类哮喘气道对臭氧的反应

• 批准号: 8325218
• 负责人: W Michael Foster
• 金额: $ 35.55万
• 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/8325218
• 关键词: Acetylcysteine; Air; Air Pollutants; Alleles; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Antioxidants; Asthma; Attenuated; Bacterial Infections; Bacterial Pneumonia; Binding; Biochemical; Biochemistry; Biological Assay; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Case-Control Studies; Caucasians; Caucasoid Race; Cells; Child; Chronic; Chronic Disease; Clinical; Communities; Cystic Fibrosis; Data; Databases; Deposition; Disease; Dose; Elastases; Elderly; Epidemiology; Epithelial; Ethnic Origin; Event; Exposure to; Family Study; Frequencies; Generations; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genotype; Growth; Homeostasis; Hospital Records; Host Defense; Human; Immune; Immune response; Immunologics; In Vitro; Inflammation; Inflammatory; Injury; Instruction; Integration Host Factors; Intervention; Intrinsic factor; Invaded; Knockout Mice; Laboratories; Leukocyte Elastase; Lung; Lung diseases; Measures; Metabolic; Metabolism; Minor; Modeling; Molecular; Molecular Structure; Mucous body substance; Mus; Oxidants; Oxygen; Ozone; Penetration; Permeability; Phenotype; Physiological; Production; Program Research Project Grants; Protein C Inhibitor; Proteins; Pulmonary Surfactant-Associated Protein A; Reporting; Research; Resolution; Risk; Role; Sampling; Serine Protease; Serum Albumin; Surface; Susceptibility Gene; Testing; Time; Tissues; Variant; Visit; air filter; airway inflammation; airway obstruction; base; cohort; cytokine; environmental toxicology; functional status; human subject; in vivo; injured airway; interest; lung injury; macrophage; mouse model; neutrophil; ozone exposure; pathogen; programs; protein complex; protein function; respiratory; response; therapy design; vector

The fundamental role of innate and adaptive host response is to recognize and defend against air toxics, invading antigens, pathogens or altered self components with the purpose of restoring tissue integrity and homeostasis. While resolution occurs during normal host response, an exogenous insult cannot be contained if basic defense factor(s) become dysregulated, and/or environmental-induced injury leads to tissue remodelling and chronic respiratory disease. The program will investigate a protein, surfactant protein A (SP-A) that is essential to host defense. The focus on SP-A narrows in on structural and metabolic changes regulated by host factors and/or oxidative changes in asthma that may reduce the ability of the protein to defend the host from environmental challenges such as bacterial infection and exposure to the prototypal air pollutant, ozone. Exposures to these agents exacerbate asthma phenotypes: airflow obstruction, airway hyperpermability, and mucus hypersecretion. Case control studies associate ambient ozone levels with reduced lung growth in children, and retrospective review of hospital records suggest increased ER visits by subjects with asthma, both young and elderly, due to exacerbation of their airway disease, concurrent with ozone exposure. Research Aims will test the hypothesis that the most common polymorphism of SP-A (rs1965708) dysregulates the protein's ability to protect the respiratory epthelial surfaces of humans from ozone-induced oxidative injury. The proposed research is human based and applied. Aim 1 will determine if asthmatics are differentially responsive to ozone, and is senstivity to ozone dependent or modulated by the SP-A 223 polymorphism. Aim 2 will determine if structural and biochemical changes in the SP-A protein associate with the SP-A 223 polymorphism, and do these changes alter the biologic function of the protein. Aim 3 will investigate in mouse models of epithelial injury, and depletion of SP-A if anti-oxidant intervention, or repletion with SP-A, respectively can attentuate the oxidative effects of ozone, and protect SP-A. The research plan is at the interface of clinical asthma and environmental toxicology and will identify genetic factors that are intrinsic to oxidant induced lung injury, and has the potential to establish the functional status of the SP-A 223 polymorphism. Our extensive data base of healthy subjects supports the plan to study the most common polymorphism of the SP- A2 gene, and investigate its association in asthmatic subjects who sustain airway injury and increases in epithelial permeability during exposure to ozone.

宿主的先天性和适应性反应的基本作用是识别和防御空气毒物， 入侵抗原、病原体或改变的自身成分，目的是恢复组织完整性， 体内平衡虽然消退发生在正常宿主反应期间，但外源性损伤不能被 如果基本防御因子变得失调，和/或环境诱导的损伤导致 组织重塑和慢性呼吸道疾病。该计划将研究一种蛋白质，表面活性剂蛋白 A（SP-A）对宿主防御至关重要。对SP-A的关注缩小到结构和代谢上 由宿主因素调节的变化和/或哮喘中的氧化变化，其可能降低 蛋白质保护宿主免受环境挑战，如细菌感染和暴露于 空气污染物的原型臭氧暴露于这些药物会加剧哮喘表型：气流 阻塞、气道通透性过高和粘液分泌过多。 病例对照研究将环境臭氧水平与儿童肺部生长减少联系起来， 一项回顾性的医院记录显示，哮喘患者的急诊就诊率增加， 和老年人，由于他们的呼吸道疾病恶化，同时臭氧暴露。研究旨在 将检验SP-A（rs 1965708）最常见的多态性失调蛋白的假设， 保护人类呼吸道上皮表面免受臭氧诱导的氧化损伤的能力。 这项研究是以人为本和应用的。目标1将确定哮喘患者是否与 对臭氧敏感，并且对臭氧敏感依赖于SP-A 223多态性或由SP-A 223多态性调节。目的 2将确定SP-A蛋白的结构和生化变化是否与SP-A 223相关 多态性，这些变化是否改变了蛋白质的生物学功能。Aim 3将在 上皮损伤的小鼠模型，以及如果抗氧化剂干预SP-A的耗尽，或用SP-A补充， 均能减弱臭氧的氧化作用，保护SP-A。 该研究计划是在临床哮喘和环境毒理学的接口，并将确定 遗传因素是氧化剂诱导的肺损伤的内在因素，并有可能建立 SP-A 223多态性的功能状态。我们广泛的健康受试者数据库支持 计划研究SP-A2基因最常见的多态性，并调查其与 哮喘受试者在暴露于 臭氧