Washington University School of Medicine, St. Louis, MO 63110, USA.
Am J Respir Crit Care Med. 2011 Apr 1;183(7):876-84. doi: 10.1164/rccm.201005-0718OC. Epub 2010 Nov 5.
Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction.
To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples.
Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury.
Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage.
These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).
基质金属蛋白酶-9（MMP-9）是一种由激活的巨噬细胞产生的弹性蛋白酶内肽酶，可能参与了人类肺气肿的发展，并且可以用现有的化合物来抑制。小鼠模型已经证明，过量的 MMP-9 产生会导致永久性的肺泡破坏。
利用 MMP-9 基因敲除小鼠和人类样本确定 MMP-9 是否会导致香烟烟雾引起的肺气肿。
使用主流烟雾暴露模型分析小鼠肺部的炎症和气腔扩大情况。通过激光捕获显微切割从肺气肿患者中分离出巨噬细胞的 mRNA。从有 30 包年以上吸烟史的患者中分离出血液单核细胞的 mRNA。通过定量聚合酶链反应（PCR）确定人类基因表达，并与通过自动计算机断层扫描分析确定的肺气肿严重程度进行比较。测定血浆克拉拉细胞分泌蛋白和表面活性剂蛋白-D 以衡量持续的肺损伤。
缺乏 MMP-9 的小鼠发展出与同基因匹配对照小鼠相同程度的香烟烟雾引起的炎症和气腔扩大。巨噬细胞是人类肺气肿标本中 MMP-9 产生的主要来源，在有和没有肺气肿的肺区域中存在相似数量的巨噬细胞 MMP-9 mRNA。尽管 MMP-9 与持续的肺损伤标志物无相关性，但在肺气肿严重程度较高的个体中，循环单核细胞产生更多的 MMP-9。
这些结果表明，吸烟的人类中的 MMP-9 与暴露于烟雾的小鼠相似，在肺气肿的肺中存在 MMP-9，但与肺气肿无关。在吸烟的人类的肺气肿机制在某种程度上与小鼠模型相似的情况下，这些数据表明，特异性抑制 MMP-9 不太可能成为香烟烟雾引起的肺气肿的有效治疗方法。该临床试验已在 www.clinicaltrials.gov 上注册（NCT 00757120）。
