Precision Targeting of the Plasminogen Activator Inhibitor-1 Mechanism Increases Efficacy of Fibrinolytic Therapy in Empyema

Plasminogen activator inhibitor-1 (PAI-1) is an endogenous irreversible inhibitor of tissue-type (tPA) and urokinase (uPA) plasminogen activators. PAI-1-targeted fibrinolytic therapy (PAI-1-TFT) is designed to decrease the therapeutic dose of tPA and uPA to attenuate the risk of bleeding and other complications. The docking site peptide (DSP) is a part of the PAI-1 reactive center loop, which interacts with plasminogen activators, thus affecting the PAI-1 mechanism. We used DSP for PAI-1-TFT in two rabbit models: chemically-induced pleural injury and Streptococcus pneumoniae induced empyema. PAI-1-TFT with DSP combined with single chain uPA or tPA resulted in an up to 8-fold decrease in the minimal effective therapeutic dose of plasminogen activator and induced no bleeding. An increase in the level of PAI-1 in infectious pleural injury, when compared to chemically-induced injury, coincided with an increase in the minimal effective dose of plasminogen activator and DSP. PAI-1 is a valid molecular target in S. pneumoniae empyema model in rabbits, which closely recapitulates key characteristics of empyema in humans. Low dose PAI-1-TFT is a novel precise interventional strategy that may improve fibrinolytic therapy of empyema in clinical practice.