Regulation of plasminogen activator inhibitor-1 and urokinase by hyaluronan fragments in mouse macrophages

Pulmonary inflammation and fibrosis are characterized by increased turnover and production of the extracellular matrix as well as an impairment of lun g fibrinolytic activity. Although fragments of the extracellular matrix com ponent hyaluronan induce macrophage production of inflammatory mediators, t he effect of hyaluronan on the fibrinolytic mediators plasminogen activator inhibitor (PAI)-1 and urokinase-type plasminogen activator (uPA) is unknow n. This study demonstrates that hyaluronan fragments augment steady-state m RNA, protein, and inhibitory activity of PAI-1 as well as diminish the base line levels of uPA mRNA and inhibit uPA activity in an alveolar macrophage cell line. Hyaluronan fragments alter macrophage expression of PAI-1 and uP A at the level of gene transcription. Similarly, hyaluronan fragments augme nt PAI-1 and diminish uPA mRNA levels in freshly isolated inflammatory alve olar macrophages from bleomycin-treated rats. These data suggest that hyalu ronan fragments influence alveolar macrophage expression of PAI-1 and uPA a nd may be a mechanism for regulating fibrinolytic activity during lung infl ammation.