Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Abstract

The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERK-dependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.