Smoking susceptibility and pathogenesis of pulmonary emphysema

吸烟是慢性阻塞性肺疾病（COPD）的主要原因，并且通常认为中性粒细胞和/或巨噬细胞释放的蛋白酶参与肺气肿的发展。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。使用支气管肺泡灌洗（BAL）比较经CT扫描发现的具有肺气肿的无症状吸烟者与具有类似吸烟史但没有肺气肿的个体，我们已经证明：（1）在具有亚临床肺气肿的受试者中，BALF液中嗜中性粒细胞衍生的颗粒蛋白的浓度显著升高，并且NE-□ 1 PI水平与中性粒细胞趋化因子的水平相关，BALF液中IL-8水平。这些数据为中性粒细胞参与提供了证据，其中IL-8可能在发展的早期阶段发挥关键作用。 关于我们 肺气肿已知支气管上皮是IL-8的潜在来源，并且在纤维化肺损伤研究中对上皮修复和结构重塑具有关键作用。虽然已知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C57 B6小鼠吸烟长达6个月，并检查末端细支气管上皮细胞的基因表达。正如我们首先建立的，我们使用激光捕获显微切割（LCM）从肺的冷冻切片中分离终末细支气管上皮细胞。从LCM获得的细胞中分离的RNA进行两轮线性扩增，以应用于高密度寡核苷酸阵列（GeneChips ; Affymetrix）。这些结果表明，多种细支气管细胞基因快速地受到吸烟的影响，并且慢性暴露改变了基因谱，提供了支气管上皮在COPD发病机制中的分子信息。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