Adaptive glutathione responses to cigarette smoke in COPD

慢性阻塞性肺病患者对香烟烟雾的适应性谷胱甘肽反应

• 批准号: 7383987
• 负责人: Brian J Day
• 金额: $ 38.92万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383987
• 关键词: Accounting; Acrolein; Agonist; Animal Model; Antioxidants; Apical; Biochemical; Bronchoalveolar Lavage; Chronic; Chronic Obstructive Airway Disease; Cigarette; Cigarette Smoker; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Data; Defect; Development; Epithelial; Epithelial Cells; Etiology; Exposure to; Genetic; Glutathione; Goals; HDAC2 gene; Histone Deacetylase; Human; Hydroxyproline; In Vitro; Inflammation; Injury; Lactate Dehydrogenase; Lipids; Liquid substance; Lung; Lung Inflammation; Lung diseases; Mediating; Metabolism; Modification; Mus; Oral; Oxidants; Oxidative Stress; PPAR Pathway; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Porphyrins; Proteins; Publishing; Pulmonary Emphysema; Purpose; Risk Factors; Role; Serum; Signal Transduction; Small Interfering RNA; Smoke; Smoker; Steroids; TNF gene; Therapeutic Intervention; Tobacco; Tobacco smoke; antioxidant therapy; base; cell injury; cigarette smoke-induced; cigarette smoking; cigarette smoking; congenic; extracellular; glutathione transporter; in vivo; knock-down; lung injury; malignant breast neoplasm; morphometry; oxidation; protective effect; protein expression; response; tert-Butylhydroperoxide; tool

DESCRIPTION (provided by applicant): The overall goal of this application is to determine the role of glutathione (GSH) adaptive responses to cigarette smoke which is a major risk factor in chronic obstructive pulmonary disease (COPD). Oxidative stress has been implicated as a pathogenic factor in the etiology of COPD. However, the role of altered GSH adaptive responses to tobacco smoke and its linkage to inflammation and oxidative stress remains unexplored. COPD is a group of lung disorders that are largely self-induced by smoking tobacco. Adaptive GSH responses are variable amongst smokers and it is hypothesized smokers who are unable to develop a robust adaptive GSH response are more vulnerable to exaggerated inflammation and injury associated with tobacco smoke. Published and preliminary data suggest that oxidative modification of histone deacetylase may also interfere with GSH adaptive pathways. Based on this, an approach to either correct the GSH imbalance or diminish oxidant burden may slow the progression of COPD. The cystic fibrosis transmembrane conductance regulator (CFTR) and breast cancer related protein (BCRP) congenic KO mouse provides a unique animal models to study defective lung GSH efflux, oxidative stress, inflammation, and injury. CFTR KO mice have a 50% decrease in their steady-state lung ELF GSH levels compared to controls and have diminished adaptive GSH efflux response to oxidative stress. The specific aims are to:1) examine mechanism(s) responsible for GSH adaptive responses stimulated by cigarette smoke; 2) examine whether defective extracellular GSH adaptive responses contributes to enhanced cigarette smoke-induced lung epithelial cell oxidation and injury upon exposure to extracellular oxidants; 3) Examine whether defective GSH transport sensitizes the lung to cigarette smoke-induced oxidative stress and inflammation. These studies will elucidate the role of extracellular GSH adaptive pathways as a protective mechanism in cigarette smoke-induced lung oxidation and injury and provides unique avenues for therapeutic intervention in the progression of COPD. Project Narrative: Oxidants have been implicated as a pathogenic factor in the development of emphysema. However, the role of altered antioxidant defenses to tobacco smoke and its linkage to inflammation and oxidative injury remains unexplored. These studies will elucidate the role of antioxidant adaptive pathways as a protective mechanism in cigarette smoke-induced lung oxidation and injury and provides unique avenues for therapeutic intervention in the progression of COPD.

描述（由申请人提供）：本申请的总体目标是确定谷胱甘肽（GSH）对香烟烟雾的适应性反应的作用，香烟烟雾是慢性阻塞性肺疾病（COPD）的主要风险因素。氧化应激已被认为是COPD病因学中的致病因素。然而，谷胱甘肽对烟草烟雾的适应性反应的改变及其与炎症和氧化应激的联系的作用仍然没有被探索。慢性阻塞性肺病是一组肺部疾病，主要是由吸烟引起的。适应性GSH反应在吸烟者中是可变的，并且假设无法形成稳健的适应性GSH反应的吸烟者更容易受到与烟草烟雾相关的过度炎症和损伤的影响。已发表的和初步的数据表明，组蛋白去乙酰化酶的氧化修饰也可能干扰GSH适应性途径。基于此，纠正GSH失衡或减少氧化剂负荷的方法可能会减缓COPD的进展。囊性纤维化跨膜传导调节因子（CFTR）和乳腺癌相关蛋白（BCRP）同源基因敲除小鼠为研究肺GSH流出缺陷、氧化应激、炎症和损伤提供了独特的动物模型。与对照组相比，CFTR KO小鼠的稳态肺ELF GSH水平降低了50%，并且对氧化应激的适应性GSH外排反应减弱。具体目的是：1）检查负责由香烟烟雾刺激的GSH适应性反应的机制; 2）检查缺陷的细胞外GSH适应性反应是否有助于在暴露于细胞外氧化剂时增强香烟烟雾诱导的肺上皮细胞氧化和损伤; 3）检查缺陷的GSH转运是否使肺对香烟烟雾诱导的氧化应激和炎症敏感。这些研究将阐明细胞外GSH适应性通路作为香烟烟雾诱导的肺氧化和损伤的保护机制的作用，并为COPD进展的治疗干预提供独特的途径。项目叙述：氧化剂被认为是肺气肿发展的致病因素。然而，改变抗氧化剂防御烟草烟雾的作用及其与炎症和氧化损伤的联系仍然未被探索。这些研究将阐明抗氧化适应性途径作为香烟烟雾诱导的肺氧化和损伤的保护机制的作用，并为COPD进展的治疗干预提供独特的途径。