Silica Induces Plasminogen Activator Inhibitor-1 Expression through a MAPKs/AP-1-Dependent Mechanism in Human Lung Epithelial Cells.

ABSTRACT Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the silica-induced pulmonary fibrosis. The effect of silica on the expression of PAI-1 was investigated in human lung epithelial cells (A549). Silica induced PAI-1 expression in a concentration-(50-200 mug/mL) and time-(4-24 h) dependent manner in A549 cells. Furthermore, the roles of mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathways in silica-induced PAI-1 expression were examined. We found that silica (200 mug/mL) treatment for 4 to 24 h resulted in AP-1 activation in A549 cells. Cells were pretreated with the AP-1 inhibitor curcumin (10, 25, 50 muM), and silica-induced PAI-1 expression was reduced by 20%, 63%, and 65%, respectively. In addition, dominant-negative mutant c-Jun (TAM67) down-regulated silica-induced PAI-1 expression by 59%. P38 kinase inhibitor SB203580 (20 muM) and Erk inhibitor PD98059 (50 muM) suppressed silica-induced PAI-1 expression by 35% and 51%, respectively. Additionally, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by silica. The results suggest that the PAI-1 expression induced by silica may be involved in the activation of MAPKs/AP-1 signaling pathways in human lung epithelial cells.