BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN TRANSGENIC MICE THAT EITHER LACK OR OVEREXPRESS THE MURINE PLASMINOGEN-ACTIVATOR INHIBITOR-1 GENE

Impaired fibrinolytic activity within the lung is a common manifestati on of acute and chronic inflammatory lung diseases, Because the fibrin olytic system is active during repair processes that restore injured t issues to normal, reduced fibrinolytic activity may contribute to the subsequent development of pulmonary fibrosis. To examine the relations hip between the fibrinolytic system and pulmonary fibrosis, lung infla mmation was induced by bleomycin in transgenic mice that either overex pressed or were completely deficient in murine plasminogen activator i nhibitor-1 (PAI-1), 2 wk after 0.075 U of bleomycin, the lungs of tran sgenic mice overexpressing PAI-I contained significantly more hydroxy- proline (118 +/- 8 mu g) than littermate controls (70.5 +/- 8 mu g, P < 0.005), 3 wk after administration of a higher dose of bleomycin (0.1 5 U), the lung hydroxyproline content of mice completely deficient in PAI-1 (49 +/- 8 mu g) was not significantly different (P = 0.63) than that of control animals receiving saline (37 +/- 1 mu g), while hydrox yproline content was significantly increased in heterozygote (77 +/- 1 2 mu g, P = 0.06) and wild-type (124 +/- 19 mu g, P < 0.001) littermat es. These data demonstrate a direct correlation between the geneticall y determined level of PAI-1 expression and the extent of collagen accu mulation that follows inflammatory lung injury, These results strongly support the hypothesis that alterations in fibrinolytic activity infl uence the extent of pulmonary fibrosis that occurs after inflammatory injury.