Integrated research for pathogenesis and epidemiology of chronic obstructive pulmonary disease

流行病学证据表明，吸烟和衰老是慢性阻塞性肺疾病（COPD）发展的两个主要危险因素。其分子机制尚不清楚，其中涉及慢性阻塞性肺病的病理生理。呼吸道是与环境的主要界面，肺上皮和肺泡巨噬细胞是抵御香烟烟雾的第一道防线。我们发现，衰老和长期吸烟的累积效应不同程度地影响谷胱甘肽二硫化物的积累，谷胱甘肽是一种氧化形式，与BAL液中过量的羰基蛋白有关，这可能导致肺泡间隙细胞外环境中的抗氧化屏障系统受损。肺是解剖学上复杂的器官。我们首先应用激光捕获显微解剖（LCM）技术来分析吸烟肺部细胞特异性基因表达。本研究提供了细支气管上皮、巨噬细胞和肺泡隔在COPD发病机制中的分子信息。LCM与核苷酸阵列的结合提供了不同肺细胞对烟雾暴露的分子反应的令人兴奋的发现。我们特别关注控制防御机制，调节炎症，促进肺结构维持的基因群，这些基因与细胞凋亡和修复有关。COPD患者和吸烟小鼠的细胞特异性基因表达谱可以为开发新的治疗策略提供可能性，考虑到靶向部位和药物的递送。

Epidemiological evidence suggests that cigarette smoking and aging are the two major risk factors for the development of chronic obstructive pulmonary disease (COPD). The molecular mechanism is poorly understood, in which the pathophysiology of COPD is involved. Respiratory tract is the major interface to the environment and the lung epithelium and alveolar macrophages are the first line of defense against cigarette smoke. We found that cumulative effects of aging and long-term smoking differently affected the accumulation of glutathione disulfide, an oxidized form of glutathione associated with excessive carbonyl proteins in BAL fluid, which might lead to the impaired antioxidant barrier system in the extracellular milieu in alveolar space. The lungs are anatomically complex organs. We first applied laser capture microdissection (LCM) techniques to analyze cell-specific gene expression in the smoking lungs. This study provides the molecular information of bronchiolar epithelium, macrophages, and alveolar septae in the pathogenesis of COPD. The combination of LCM with nucleotide arrays offers exciting discovery of the molecular responses of different lung cells to smoke exposure. We especially focus on the groups of genes controlling the defense mechanism, regulating the inflammation, and contributing to the maintenance of lung structure, which is related to cell apoptosis and repair. The cell-specific gene expression profile in COPD patients as well as in smoking mice could open the possibilities for the development of new therapeutic strategies, considering targeted site and the delivery of drugs.