Wallace Alison M, Sandford Andrew J, English John C, Burkett Kelly M, Li Hong, Finley Richard J, Müller Nestor L, Coxson Harvey O, Paré Peter D, Abboud Raja T
University of British Columbia (UBC) James Hogg iCAPTURE Centre, St. Paul's Hospital, Vancouver, BC, Canada.
COPD. 2008 Feb;5(1):13-23. doi: 10.1080/15412550701817789.
An abnormal increase in proteolytic enzymes is thought to play a key role in pulmonary emphysema. Alveolar macrophage proteolytic enzymes include cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12, and a number of studies have implicated these proteinases in the alveolar destruction that characterizes emphysema. The aim of this study was to investigate cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12 mRNA expression in alveolar macrophages isolated from patients with varying degrees of emphysema and to correlate their level of expression with measures of emphysema. Alveolar macrophages were isolated from fifty-four patients who underwent surgical resection for lung carcinoma. The level of mRNA expression was determined using real-time PCR. Emphysema was quantified using high-resolution CT scans. Alveolar macrophages were also cultured for 24 h and 48 h; the effect of proinflammatory mediators and promoter polymorphisms on expression was analyzed. There was a significant correlation between matrix metalloproteinase 1 mRNA expression and emphysema. A higher level of matrix metalloproteinase 1 mRNA was associated with more severe emphysema. Matrix metalloproteinase 12 mRNA expression was increased in current smokers as compared with former smokers. Furthermore, there was a negative correlation between matrix metalloproteinase 12 gene expression and carbon monoxide diffusing capacity. The matrix metalloproteinase 9 C-1562T polymorphism significantly influenced matrix metalloproteinase 9 mRNA expression in alveolar macrophages. These results suggest that alveolar macrophage matrix metalloproteinase 1 and 12 may have a role in the lung structural changes leading to the development of emphysema. Furthermore, these data provide evidence to support the concept that multiple proteinases, causing both elastin and collagen degradation, are important in the pathogenesis of pulmonary emphysema.
蛋白水解酶的异常增加被认为在肺气肿中起关键作用。肺泡巨噬细胞蛋白水解酶包括组织蛋白酶L、组织蛋白酶S、基质金属蛋白酶1、9和12，多项研究表明这些蛋白酶与肺气肿特征性的肺泡破坏有关。本研究的目的是调查从不同程度肺气肿患者分离出的肺泡巨噬细胞中组织蛋白酶L、组织蛋白酶S、基质金属蛋白酶1、9和12的mRNA表达，并将它们的表达水平与肺气肿的测量指标相关联。从54例接受肺癌手术切除的患者中分离出肺泡巨噬细胞。使用实时PCR测定mRNA表达水平。使用高分辨率CT扫描对肺气肿进行量化。肺泡巨噬细胞也培养24小时和48小时；分析促炎介质和启动子多态性对表达的影响。基质金属蛋白酶1的mRNA表达与肺气肿之间存在显著相关性。基质金属蛋白酶1的mRNA水平较高与更严重的肺气肿相关。与既往吸烟者相比，现吸烟者的基质金属蛋白酶12的mRNA表达增加。此外，基质金属蛋白酶12基因表达与一氧化碳弥散能力之间存在负相关。基质金属蛋白酶9的C-1562T多态性显著影响肺泡巨噬细胞中基质金属蛋白酶9的mRNA表达。这些结果表明，肺泡巨噬细胞基质金属蛋白酶1和12可能在导致肺气肿发展的肺结构变化中起作用。此外，这些数据提供了证据支持这样的概念，即多种导致弹性蛋白和胶原蛋白降解的蛋白酶在肺气肿的发病机制中很重要。
