Published ahead of print on November 10, 2006, doi:10.1165/rcmb.2006-0106OC Am. J. Respir. Cell Mol. Biol., Volume 36, Number 4, April 2007, 480-490 A more recent version of this article appeared on April 1, 2007
Submitted on March 10, 2006 Cigarette Smoke Stimulates Matrix Metalloproteinase-2 Activity via EGR-1 in Human Lung FibroblastsWen Ning1,1 Department of Medicine, Pulmonary, Allergy and Critical Care Medicine Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Model Animal Research Center, Nanjing University, Nanjing, China, 2 Model Animal Research Center, Nanjing University, Nanjing, China, 3 Cardiovascular Research Institute and the Departments of Medicine and Anesthesia, University of California, San Francisco, CA, USA, 4 Department of Medicine, Pulmonary, Allergy and Critical Care Medicine Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States * To whom correspondence should be addressed. 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/anti-proteinase 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 COPD patients compared to 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 MMP2 mRNA and protein expression, and activity were significantly inhibited using EGR-1 siRNA or in Egr-1 null (-/-) mouse fibroblasts. Furthermore, we observed induction of 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 EGR1 dependent reveals a molecular mechanism for matrix remodeling in cigarette smoke related emphysema.
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