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, attenuating the risk of bleeding and other complications. Docking site peptide (DSP) mimics the part of the PAI-1 reactive center loop that interacts with plasminogen activators, thereby 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. These models feature different levels of inflammation and PAI-1 expression. PAI-1- TFT with DSP (2.0 mg/kg) converted ineffective doses of single chain (sc) tPA (72.5 μg/kg) and scuPA (62.5 μg/kg) into effective ones in chemically induced pleural injury. DSP (2.0 mg/kg) was ineffective in S. pneumoniae empyema, where the level of PAI-1 is an order of magnitude higher. DSP dose escalation to 8.0 mg/kg resulted in effective PAI-1- TFT with 0.25 mg/kg sctPA (1/8th of the effective dose of sctPA alone) in empyema. There was no increase in the efficacy of scuPA. PAI-1- TFT with DSP increases the efficacy of fibrinolytic therapy up to 8-fold in chemically induced (sctPA and scuPA) and infectious (sctPA) pleural injury in rabbits. PAI-1 is a valid molecular target in our model of S. pneumoniae empyema in rabbits, which closely recapitulates key characteristics of empyema in humans. Low-dose PAI-1- TFT is a novel interventional strategy that offers the potential to improve fibrinolytic therapy for empyema in clinical practice.
Funding information: National Heart, Lung, and Blood Institute, Grant/Award Number: R01HL130402. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society
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Florova, Galina; Girard, René A.; Azghani, Ali O.; Sarva, Krishna; Buchanan, Ann; Karandashova, Sophia; DeVera, Christian J.; Morris, Danna; Chamiso, Mignote; Koenig, Kathleen; Cines, Douglas B.; Idell, Steven; and Komissarov, Andrey A., "Precision targeting of the plasminogen activator inhibitor-1 mechanism increases efficacy of fibrinolytic therapy in empyema" (2021). School of Medical and Biological Sciences Faculty Publications and Presentations. Paper 2.