Published ahead of print on November 10, 2006, doi:10.1165/rcmb.2006-0106OC
© 2007 American Thoracic Society DOI: 10.1165/rcmb.2006-0106OC Cigarette Smoke Stimulates Matrix Metalloproteinase-2 Activity via EGR-1 in Human Lung FibroblastsPulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Model Animal Research Center, Nanjing University, Nanjing, China; and Cardiovascular Research Institute and the Departments of Medicine and Anesthesia, University of California, San Francisco, California Correspondence and requests for reprints should be addressed to Augustine M. K. Choi, M.D., University of Pittsburgh, Pulmonary, Allergy and Critical Care Medicine, MUH 628 NW, 3459 Fifth Ave., Pittsburgh, PA 15213. E-mail: choiam{at}upmc.edu 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 Egr-1–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.
Key Words: chronic obstructive pulmonary disease • EGR-1 • cigarette smoke extract • MMP-2 • MT1-MMP
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