Smoking susceptibility and pathogenesis of pulmonary emphysema

吸烟是慢性阻塞性肺疾病(COPD)的主要原因，中性粒细胞和/或巨噬细胞释放的蛋白水解酶参与了肺气肿的发生。目前尚不清楚为什么只有一小部分吸烟者会出现临床上明显的肺气肿，以及哪些细胞和/或蛋白酶在COPD的发病机制中起关键作用。应用支气管肺泡灌洗(BAL)技术对CT扫描发现的无症状吸烟者和无肺气肿史的吸烟者进行比较，结果表明：(1)亚临床肺气肿患者BAL液中中性粒细胞衍生颗粒蛋白浓度显著升高，且NE-1PI水平与BAL液中中性粒细胞趋化因子IL-8水平呈正相关。这些数据为中性粒细胞参与…的早期发展提供了证据，其中IL-8可能起关键作用。更多的肺气肿。细支气管上皮被认为是IL-8的潜在来源，并且在纤维化肺损伤的上皮修复和结构重塑中起着关键作用。虽然吸烟以多种方式影响肺结构和功能，但尚未对吸烟对肺基因表达的影响进行全面评估。因此，我们将C57B6小鼠置于香烟烟雾中长达6个月，并检测了终末细支气管上皮的基因表达。正如我们第一次确定的那样，我们使用激光捕获显微解剖(LCM)从冰冻的肺切片中分离出终末细支气管上皮细胞。从LCM获得的细胞中提取的RNA经过两轮线性扩增，应用于高密度寡核苷酸阵列(GeneChips；Affymetrix)。这些结果表明，吸烟可迅速影响多种细支气管壁细胞基因，慢性暴露可改变细支气管壁基因谱，为COPD发病机制中的细支气管壁提供了分子信息。较少

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and it is generally accepted that proteinases released from neutrophils and/or macrophages are involved in the development of emphysema. It remained unknown why only a small portion of smokers develops clinically apparent emphysema and which cells and/or proteinases play a key role in the pathogenesis of COPD. Using bronchoalveolar lavage (BAL) to compare asymptomatic smokers having emphysema detected by CT scans with individuals who have a similar smoking history but do not have emphysema, we have demonstrated that (1) the concentration of neutrophil-derived granular proteins are significantly elevated in BAL fluid in the subjects with subclinical emphysema, and the level of NE-□1PI correlates with the level of neutrophil chemoattractant, interleukin-8 (IL-8) in BAL fluid. These data provide evidence for neutrophil involvement, in which IL-8 might play a key role, in the early stage of development of … More pulmonary emphysema. Bronchiolar epithelium is known to be a potential source of IL-8, and has a critical role in repair of epithelium and structural remodeling as studied in fibrosing lung injuries. Although smoking is known to affect lung structure and function in diverse ways, a comprehensive assessment of smoking's effects on pulmonary gene expression has not been done. Accordingly, we have subjected C57B6 mice to the smoke of cigarettes for up to 6 months and examined gene expression of terminal bronchiolar epithelium. As we first established, we used laser capture microdissection (LCM) to isolate terminal bronchiolar epithelial cells from frozen sections of lungs. The RNA isolated from LCM-obtained cells was subjected to two rounds of linear amplification to apply to high-density oligonucleotide arrays (GeneChips ; Affymetrix). These results show theat a variety of bronchiolar cell genes are affected quickly by smoking and that the gene profile is changed by chronic exposure, providing the molecular information of bronchiolar epithelium in the pathogenesis of COPD. Less