Cigarette smoke stimulates matrix metalloproteinase-2 activity via EGR-1 in human lung fibroblasts
Cigarette smoke stimulates matrix metalloproteinase-2 activity via EGR-1 in human lung fibroblasts
复制标题
香烟烟雾通过 EGR-1 刺激人肺成纤维细胞中的基质金属蛋白酶-2 活性
DOI：
10.1165/rcmb.2006-0106oc
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发表时间：
2007-04-01
影响因子：
6.4
通讯作者：
Choi, Augustine M. K.
中科院分区：
文献类型：
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作者：
Ning, Wen;Dong, Yingying;Choi, Augustine M. K.
吸烟是慢性阻塞性肺疾病（COPD）的主要危险因素。最近关于肺气肿患者肺中基质金属蛋白酶-2（MMP-2）升高的报道支持COPD发病机制中蛋白酶/抗蛋白酶失衡的范例。我们试图确定烟雾激活的信号通路，并确定负责肺气肿相关MMP-2表达的分子。在这项研究中，我们表明，香烟烟雾提取物（CSE）诱导MMP-2蛋白的表达和MMP-2明胶酶活性增加正常肺成纤维细胞。我们先前鉴定了一种转录因子，早期生长反应1（EGR-1），与对照吸烟者相比，在COPD患者的肺组织中具有稳健的表达。在这里，用CSE处理成纤维细胞导致EGR-1 mRNA和蛋白以剂量和时间依赖性方式显著诱导，伴随着EGR-1结合活性增加。使用EGR-1小干扰RNA（siRNA）或Egr 1-null（-/-）小鼠成纤维细胞显著抑制CSE诱导的MMP-2 mRNA和蛋白表达和活性。此外，我们观察到诱导膜1型基质金属蛋白酶（MT 1-MMP），它有一个EGR-1结合位点的启动子，在CSE处理的原代正常肺成纤维细胞。EGR-1 siRNA抑制CSE引起的MT 1-MMP表达和MMP-2活化。在CSE处理的成纤维细胞中观察到有丝分裂原活化蛋白激酶的快速活化。ERK 1/2 MAPK的化学抑制剂，而不是p38和JNK，降低CSE诱导的EGR-1蛋白表达和MMP-2活性的成纤维细胞。CSE对肺成纤维细胞MMP-2和MT 1-MMP的诱导是EGR-1依赖性的，这一发现揭示了香烟烟雾相关肺气肿中基质重塑的分子机制。
Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Recent reports of increased matrix metalloproteinase-2 (MMP-2) in lungs of patients with emphysema support the paradigm of proteinase/antiproteinase imbalance in the pathogenesis of COPD. We sought to define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-2 expression. In this study, we show that cigarette smoke extract (CSE) induced MMP-2 protein expression and increased MMP-2 gelatinase activity of normal lung fibroblasts. We previously identified a transcription factor, early growth response 1 (EGR-1), with robust expression in the lung tissues of patients with COPD compared with control smokers. Here, the treatment of fibroblasts with CSE resulted in marked induction of EGR-1 mRNA and protein in a dose- and time-dependent manner, accompanied by increased EGR-1 binding activity. CSE-induced MMP-2 mRNA and protein expression and activity were significantly inhibited using EGR-1 small interfering RNA (siRNA) or in Egr1-null(-/-) mouse fibroblasts. Furthermore, we observed induction of membrane type 1 matrix metalloproteinase (MT1-MMP), which has an EGR-1-binding site on its promoter, in CSE-treated primary normal lung fibroblasts. The concomitant MT1-MMP expression and MMP-2 activation by CSE are inhibited by EGR-1 siRNA. Rapid activation of mitogen-activated protein kinases was observed in CSE-treated fibroblasts. Chemical inhibitors of ERK1/2 MAPK, but not of p38 and JNK, decreased CSE-induced EGR-1 protein expression and MMP-2 activity of fibroblasts. The identification that induction of MMP-2 and MT1-MMP by CSE from lung fibroblasts is EGR-1-dependent reveals a molecular mechanism for matrix remodeling in cigarette smoke-related emphysema.