To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from smokers who are at risk (GOLD-0) to tissues from smokers that have developed moderate (GOLD-2) COPD. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.5-fold upor down-regulated). Microarray analysis using the same RNA source detected 261 transcripts that were differentially expressed to a significant degree between GOLD-2 and GOLD-0 smokers. We confirmed the altered expression of a select number of genes using real-time quantitative RT-PCR. These genes encode for transcription factors (EGR1, FOS), growth factors or related proteins (CTGF, CYR61, CX3CL1, TGFB1, PDGFRA) and extracellular matrix protein (COL1A1). Immunofluorescence studies on the same lung specimens localized the expression of Egr-1, CTGF, and Cyr61 to alveolar epithelial cells, airway epithelial cells, stromal cells, and inflammatory cells of GOLD-2 smokers. For biological validation, we focused on the upstream transcription factor Egr-1. Exposure of lung fibroblasts (NL) to cigarette smoke extract (CSE) resulted in marked induction of Egr-1 mRNA protein in a dose-and time-dependent manner, accompanied by increases of Egr-1 binding activity. Egr-1 siRNA to knockout Egr-1 expression inhibited CSE-induced MMP-2 activation. Rapid activation of mitogen-activated protein kinases (Erk1/2, p38, and JNK MAPK) were observed in CSE-treated NL cells. Chemical inhibitors of Erk1/2 MAPK (U0126 and PD98059), but not the chemical inhibitors of p38 and JNK MAPK (SB203580 and JNK inhibitor II), abolished CSE (20%)-induced Egr-1 protein expression and decreased CSE (20%)-induced MMP-2 gelatinase activity of NL9 cells. The identification that induction of MMP-2 by CSE from lung fibroblast cells is Erk1/2-Egr1–dependent reveals a molecular mechanism for excessive matrix remodeling in cigarette smoke–related emphysema.