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Smoking susceptibility and pathogenesis of pulmonary emphysema

吸烟易感性与肺气肿发病机制

基本信息

批准号：
13470125
负责人：
NISHIMURA Masaharu
金额：
$ 9.47万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470125/
关键词：
smoking epithelial cell gene genechip adenovirus pulmonary emphysema neutrophil macrophage genechip アデノウイルス好中球

项目摘要

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

吸烟是慢性阻塞性肺疾病（COPD）的主要原因，人们普遍认为中性粒细胞和/或巨噬细胞释放的蛋白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CT扫描发现的无症状吸烟者肺气肿与有相似吸烟史但没有肺气肿的个体，我们已经证明(1)在亚临床肺气肿受试者的BAL液中中性粒细胞衍生颗粒蛋白的浓度显著升高，并且NE-□1PI的水平与BAL液中中性粒细胞趋化剂白细胞介素-8 （IL-8）的水平相关。这些数据提供了中性粒细胞参与的证据，其中IL-8可能在早期发展阶段发挥关键作用。已知细支气管上皮是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关键作用。虽然已知吸烟会以多种方式影响肺部结构和功能，但尚未对吸烟对肺部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，并检测终细支气管上皮的基因表达。正如我们最初建立的那样，我们使用激光捕获显微解剖（LCM）从肺冷冻切片中分离终细支气管上皮细胞。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受到吸烟的快速影响，并且基因谱随着慢性暴露而改变，为细支气管上皮在COPD发病机制中的分子信息提供了依据。少