Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema
The incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A <i>Streptococcus pneumoniae<...
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| Format: | Article |
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MDPI AG
2023-05-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/5/1498 |
| _version_ | 1797598663577436160 |
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| author | Galina Florova Christian J. De Vera Rebekah L. Emerine René A. Girard Ali O. Azghani Krishna Sarva Jincy Jacob Danna E. Morris Mignote Chamiso Steven Idell Andrey A. Komissarov |
| author_facet | Galina Florova Christian J. De Vera Rebekah L. Emerine René A. Girard Ali O. Azghani Krishna Sarva Jincy Jacob Danna E. Morris Mignote Chamiso Steven Idell Andrey A. Komissarov |
| author_sort | Galina Florova |
| collection | DOAJ |
| description | The incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A <i>Streptococcus pneumoniae</i>-induced rabbit model of chronic empyema recapitulates the progression, loculation, fibrotic repair, and pleural thickening of human disease. Treatment with single chain (sc) urokinase (scuPA) or tissue type (sctPA) plasminogen activators in doses 1.0–4.0 mg/kg were only partially effective in this model. Docking Site Peptide (DSP; 8.0 mg/kg), which decreased the dose of sctPA for successful fibrinolytic therapy in acute empyema model did not improve efficacy in combination with 2.0 mg/kg scuPA or sctPA. However, a two-fold increase in either sctPA or DSP (4.0 and 8.0 mg/kg or 2.0 and 16.0 mg/kg sctPA and DSP, respectively) resulted in 100% effective outcome. Thus, DSP-based Plasminogen Activator Inhibitor 1-Targeted Fibrinolytic Therapy (PAI-1-TFT) of chronic infectious pleural injury in rabbits increases the efficacy of alteplase rendering ineffective doses of sctPA effective. PAI-1-TFT represents a novel, well-tolerated treatment of empyema that is amenable to clinical introduction. The chronic empyema model recapitulates increased resistance of advanced human empyema to fibrinolytic therapy, thus allowing for studies of muti-injection treatments. |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T03:24:19Z |
| publishDate | 2023-05-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-51161308453244e58ccac30c3ac696e82023-11-18T02:52:27ZengMDPI AGPharmaceutics1999-49232023-05-01155149810.3390/pharmaceutics15051498Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic EmpyemaGalina Florova0Christian J. De Vera1Rebekah L. Emerine2René A. Girard3Ali O. Azghani4Krishna Sarva5Jincy Jacob6Danna E. Morris7Mignote Chamiso8Steven Idell9Andrey A. Komissarov10The Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Biology, University of Texas at Tyler, Tyler, TX 75799, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler (UTHSCT), Tyler, TX 75708, USAThe incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A <i>Streptococcus pneumoniae</i>-induced rabbit model of chronic empyema recapitulates the progression, loculation, fibrotic repair, and pleural thickening of human disease. Treatment with single chain (sc) urokinase (scuPA) or tissue type (sctPA) plasminogen activators in doses 1.0–4.0 mg/kg were only partially effective in this model. Docking Site Peptide (DSP; 8.0 mg/kg), which decreased the dose of sctPA for successful fibrinolytic therapy in acute empyema model did not improve efficacy in combination with 2.0 mg/kg scuPA or sctPA. However, a two-fold increase in either sctPA or DSP (4.0 and 8.0 mg/kg or 2.0 and 16.0 mg/kg sctPA and DSP, respectively) resulted in 100% effective outcome. Thus, DSP-based Plasminogen Activator Inhibitor 1-Targeted Fibrinolytic Therapy (PAI-1-TFT) of chronic infectious pleural injury in rabbits increases the efficacy of alteplase rendering ineffective doses of sctPA effective. PAI-1-TFT represents a novel, well-tolerated treatment of empyema that is amenable to clinical introduction. The chronic empyema model recapitulates increased resistance of advanced human empyema to fibrinolytic therapy, thus allowing for studies of muti-injection treatments.https://www.mdpi.com/1999-4923/15/5/1498PAI-1serpinempyemachronicmolecular targetpreclinical |
| spellingShingle | Galina Florova Christian J. De Vera Rebekah L. Emerine René A. Girard Ali O. Azghani Krishna Sarva Jincy Jacob Danna E. Morris Mignote Chamiso Steven Idell Andrey A. Komissarov Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema Pharmaceutics PAI-1 serpin empyema chronic molecular target preclinical |
| title | Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema |
| title_full | Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema |
| title_fullStr | Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema |
| title_full_unstemmed | Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema |
| title_short | Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema |
| title_sort | targeting the pai 1 mechanism with a small peptide increases the efficacy of alteplase in a rabbit model of chronic empyema |
| topic | PAI-1 serpin empyema chronic molecular target preclinical |
| url | https://www.mdpi.com/1999-4923/15/5/1498 |
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