Adaptive glutathione responses to cigarette smoke in 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)的主要危险因素。氧化应激已被认为是慢性阻塞性肺疾病的病因之一。然而，改变GSH对烟草烟雾的适应性反应的作用及其与炎症和氧化应激的联系仍未被探索。COPD是一组肺部疾病，主要是由吸烟引起的。适应性GSH反应在吸烟者中是不同的，假设吸烟者不能形成强大的适应性GSH反应，则更容易受到与烟草烟雾相关的夸大炎症和伤害的影响。已发表的和初步的数据表明，组蛋白脱乙酰酶的氧化修饰也可能干扰GSH适应途径。基于此，纠正GSH失衡或减轻氧化负担的方法可能会减缓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)基因KO小鼠为研究肺GSH外流缺陷、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，CFTRKO小鼠的稳态肺ELF GSH水平降低了50%，并降低了对氧化应激的适应性GSH外流反应。其具体目的是：1)研究香烟烟雾刺激GSH适应性反应的机制(S)；2)检测细胞外GSH适应性反应缺陷是否有助于香烟烟雾诱导的肺上皮细胞氧化和暴露于细胞外氧化剂时的损伤；3)检测GSH转运缺陷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适应性通路在香烟烟雾诱导的肺氧化和损伤中的保护机制，并为COPD的进展提供独特的治疗干预途径。项目简介：氧化剂被认为是肺气肿发展的致病因素。然而，改变的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未被探索。这些研究将阐明抗氧化适应性通路在香烟烟雾诱导的肺氧化和损伤中作为保护机制的作用，并为COPD进展的治疗干预提供独特的途径。

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.