An imbalance between proteases and anti-proteases is believed to play an important role in the pathogenesis of emphysema. In this study, we explored the hypothesis that cigarette smoke can alter tissue structure through an effect on the release of matrix metalloproteinase-1 (MMP-1) and type I tissue inhibitor of metalloproteinases (TIMP-1). Cigarette smoke extract (CSE) significantly stimulated pro-MMP-1 production (determined by ELISA and immunoblots) and mRNA expression (by real-time RT-PCR) by human fetal lung fibroblasts (HFL-1) in a concentration-dependent manner (2.5-10%). High concentrations of CSE (10%) could potentially activate the latent form of MMP-1 as the high molecular weight (52 kDa) form was converted into a low molecular weight (42 kDa) form consistent with active MMP-1. TIMP-1 production, however, was not significantly altered by the concentrations of CSE tested. After 30 min exposure, CSE significantly induced ERK1/2 phosphorylation, which then gradually decreased from 90 minutes to 3 hours. PD98059, a specific inhibitor of ERK-MAPK, significantly blocked the CSE effect on ERK1/2 phosphorylation. Furthermore, PD98059 significantly inhibited the CSE effect on MMP-1 production and mRNA expression by fibroblasts. These results suggest that cigarette smoke stimulates production and likely activates MMP-1 through activating ERK1/2 signal transduction pathway. By inducing MMP-1, cigarette smoke may result in excess tissue destruction and contribute to the development of emphysema.