Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice

Mice deleted for the plasminogen activator inhibitor-1 (PAI-1) gene are rel atively protected from developing pulmonary fibrosis induced by bleomycin. We hypothesized that PAI-1 deficiency reduces fibrosis by promoting plasmin ogen activation and accelerating the clearance of fibrin matrices that accu mulate within the damaged lung. In support of this hypothesis, we found tha t the lungs of PAI-1(-/-) mice accumulated less fibrin after injury than wi ld-type mice, due in part to enhanced fibrinolytic activity. To further sub stantiate the importance of fibrin removal as the mechanism by which PAI-1 deficiency limited bleomycin-induced fibrosis, bleomycin was administered t o mice deficient in the gene for the A alpha -chain of fibrinogen (fib). Co ntrary to our expectation, fib(-/-) mice developed pulmonary fibrosis to a degree similar to fib(+/-) littermate controls, which have a plasma fibrino gen level that is 70% of that of wild-type mice. Although elimination of fi brin from the lung was not in itself protective, the beneficial effect of P AI-1 deficiency was still associated with proteolytic activity of the plasm inogen activation system. In particular, inhibition of plasmin activation a nd/or activity by tranexamic acid reversed both the accelerated fibrin clea rance and the protective effect of PAI-1 deficiency. We conclude that prote ction from fibrosis by PAI-1 deficiency is depend ent upon increased proteo lytic activity of the plasminogen activation system; however, complete remo val of fibrin is not sufficient to protect the lung.