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Am J Respir Cell Mol Biol. 2007 Apr;36(4):480-90. Epub 2006 Nov 10.

Cigarette smoke stimulates matrix metalloproteinase-2 activity via EGR-1 in human lung fibroblasts.

Author information

1
University of Pittsburgh, Pulmonary, Allergy and Critical Care Medicine, MUH 628 NW, 3459 Fifth Ave., Pittsburgh, PA 15213, USA.

Abstract

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.

PMID:
17099140
PMCID:
PMC1899323
DOI:
10.1165/rcmb.2006-0106OC
[Indexed for MEDLINE]
Free PMC Article

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