We hypothesized that inhibition of matrix-degrading metalloproteinases (MMPs) accounts for a portion of the pleural fibrosis and adhesions of tetracycline pleurodesis. MMPs recently have been described in pleural fluid from patients with both exudative and transudative effusions. Since tetracyclines are recognized inhibitors of other metalloproteinases, we investigated their inhibitory capacity in pleural fluid. High concentrations of several different tetracyclines reduced MMP activity of pleural fluid by more than 75 percent. Lower concentrations (< or = 1 mg/ml) had only modest inhibitory effects. High concentration of of tetracyclines also inhibited cell synthesis of MMPs, in vitro, but other measures of vital cell function were also impaired. We conclude that tetracyclines are effective inhibitors of MMP activity in pleural fluid and may also reduce synthesis of MMPs via non specific cell injury. These data suggest a possible mechanism to account for tetracycline pleurodesis; ie, an inhibition of MMP activity in pleural fluid.