PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN ACUTE HYPEROXIC MOUSE LUNG INJURY

Hyperoxia-induced lung disease is associated with prominent intraalveo lar fibrin deposition, Fibrin turnover is tightly regulated by the con certed action of proteases and antiproteases, and inhibition of plasmi n-mediated proteolysis could account for fibrin accumulation in lung a lveoli. We show here that lungs of mice exposed to hyperoxia overprodu ce plasminogen activator inhibitor-1 (PAI-1), and that PAI-1 upregulat ion impairs fibrinolytic activity in the alveolar compartment. To expl ore whether increased PAI-1 production is a causal or only a correlati ve event for impaired intraalveolar fibrinolysis and the development o f hyaline membrane disease, we studied mice genetically deficient in P AI-1. We found that these mice fail to develop intraalveolar fibrin de posits in response to hyperoxia and that they are more resistant to th e lethal effects of hyperoxic stress, These observations provide clear and novel evidence for the pathogenic contribution of PAI-1 in the de velopment of hyaline membrane disease. They identify PAI-1 as a major deleterious mediator of hyperoxic lung injury.