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.

先天和自适应宿主反应的基本作用是认识并防御空气毒物， 入侵抗原，病原体或改变的自我成分，目的是恢复组织完整性和 稳态。尽管在正常宿主反应期间发生分辨率，但外源性侮辱不能是 包含如果基本防御因素失调，并且/或环境诱发的伤害导致 组织重塑和慢性呼吸道疾病。该程序将研究蛋白质表面活性剂蛋白 （SP-A）对于举办防御至关重要。对SP-A的重点缩小在结构和代谢上 受宿主因素调节和/或哮喘的氧化变化所调节的变化可能会降低 蛋白质捍卫宿主免受环境挑战，例如细菌感染和暴露于 原型空气污染物，臭氧。暴露于这些代理商加剧哮喘表型：气流 阻塞，气道高可渗透性和粘液过度分泌。 案例控制研究将环境臭氧水平与儿童的肺部生长降低相关， 对医院记录的回顾性回顾表明，哮喘受试者的急诊室访问增加，都年轻 而且，由于其气道疾病加剧，老年人与臭氧暴露同时发生。研究目的 将检验以下假设：SP-A（RS1965708）最常见的多态性使蛋白质失调 保护人类免受臭氧诱导的氧化损伤的呼吸道表面的能力。 拟议的研究是基于人类的和应用的。 AIM 1将确定哮喘病是否是差异的 对臭氧的反应，是对臭氧依赖性或受SP-A 223多态性调节的剂量。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 多态性并进行这些变化改变了蛋白质的生物学功能。 AIM 3将在 如果抗氧化剂干预或对SP-A的递质，则上皮损伤的小鼠模型和SP-A的耗竭， 分别可以注意臭氧的氧化作用，并保护SP-A。 该研究计划位于临床哮喘和环境毒理学的界面，将确定 氧化剂诱导的肺损伤的遗传因素，并且有可能建立 SP-A 223多态性的功能状态。我们的大量健康受试者的数据库支持 计划研究SP-A2基因最常见的多态性，并研究其在 在暴露期间，维持气道损伤并增加上皮渗透性的哮喘患者 臭氧。