Home
|
Inbox
|
Search
|
View Abstract
Striking Difference in the Effects of a Docking Site Peptide on Fibrinolytic Therapy of Infectious and Chemical Pleural Injury in Rabbits
Description
.abstract img { width:300px !important; height:auto; display:block; text-align:center; margin-top:10px } .abstract { overflow-x:scroll } .abstract table { width:100%; display:block; border:hidden; border-collapse: collapse; margin-top:10px } .abstract td, th { border-top: 1px solid #ddd; padding: 4px 8px; } .abstract tbody tr:nth-child(even) td { background-color: #efefef; } .abstract a { overflow-wrap: break-word; word-wrap: break-word; }
A3954 - Striking Difference in the Effects of a Docking Site Peptide on Fibrinolytic Therapy of Infectious and Chemical Pleural Injury in Rabbits
Author Block: A. Komissarov1, A. O. Azghani2, A. Buchanan3, M. Chamiso1, R. Girard1, K. Sarva1, A. R. Tvinnereim1, K. Koenig1, D. B. Cines4, S. Idell1, G. Florova1; 1University of Texas Health Science Center at Tyler, Tyler, TX, United States, 2University of Texas At Tyler, Tyler, TX, United States, 3Vivarium, University of Texas Health Science Center at Tyler, Tyler, TX, United States, 4Pathology and Laboratory Medicine, Perelman-University of Pensilvania, School of Medicine, Philadelphia, PA, United States.
Rationale: Targeted fibrinolytic therapy (FT) is designed to decrease the therapeutic dose of a plasminogen activator and attendant risk of the bleeding complications. The Docking Site Peptide (DSP) EEIIMD is a part of the plasminogen activator inhibitor 1 (PAI-1) reactive center loop. Previously, we demonstrated that DSP (2.0 mg/kg) protects urokinase (uPA) and tissue type (tPA) plasminogen activators during FT of chemically induced pleural injury in rabbits. As a result, single chain (sc) tPA and scuPA become effective at a dose of 60-70 µg/kg (an 8 and 2 fold increase in their efficacy, respectively). Therefore, we used DSP as a novel FT adjunct the Streptococcus pneumoniae pleural injury model.
Methods: Pleural injury was induced by intrapleural injection of 1×108cfu of S. pneumoniae. The development of pleural injury was monitored by ultrasonography and pulmonary function tests. Animals were treated with minimally effective doses (MID; 0.5 mg/kg) of sctPA and scuPA. Animals were euthanized at 24h after FT and the outcomes were assessed postmortem. LC/MS/MS mass spectrometry was employed to monitor DSP in samples of pleural fluid collected at 10, 20 40 min and at 24h after treatment.
Results: DSP (2 mg/kg) did not increase the efficacy of a MID of scuPA when treating acute S. pneumoniae empyema. In contrast, there was a trend towards improving therapeutic outcomes after treatment with a MID of sctPA (0. 5 mg/kg). A two-fold increase in the dose of DSP (4 mg/kg) further improved therapeutic outcomes with a MID of sctPA. An increase in the efficacy of FT with a MID of sctPA by DSP was accompanied by an improvement in pulmonary function - a decrease in resistance and increase in compliance. However, the combination of 4 mg/kg of DSP with one half of a MID of sctPA (0.25 mg/kg) was ineffective. DSP was detected in pleural fluids collected at 0-40 min by LC/MS/MS mass spectrometry.
Conclusions: The DSP, which drastically improved the efficacy of FT with scuPA and sctPA in chemically-induced pleural injury, was ineffective with a MID of scuPA and only moderately effective with a MID of sctPA in S. pneumoniae empyema. Thus, different molecular mechanisms of fibrinolysis likely govern the effects of DSP on FT in chemical and infectious pleural injury.
Author Block: A. Komissarov1, A. O. Azghani2, A. Buchanan3, M. Chamiso1, R. Girard1, K. Sarva1, A. R. Tvinnereim1, K. Koenig1, D. B. Cines4, S. Idell1, G. Florova1; 1University of Texas Health Science Center at Tyler, Tyler, TX, United States, 2University of Texas At Tyler, Tyler, TX, United States, 3Vivarium, University of Texas Health Science Center at Tyler, Tyler, TX, United States, 4Pathology and Laboratory Medicine, Perelman-University of Pensilvania, School of Medicine, Philadelphia, PA, United States.
Rationale: Targeted fibrinolytic therapy (FT) is designed to decrease the therapeutic dose of a plasminogen activator and attendant risk of the bleeding complications. The Docking Site Peptide (DSP) EEIIMD is a part of the plasminogen activator inhibitor 1 (PAI-1) reactive center loop. Previously, we demonstrated that DSP (2.0 mg/kg) protects urokinase (uPA) and tissue type (tPA) plasminogen activators during FT of chemically induced pleural injury in rabbits. As a result, single chain (sc) tPA and scuPA become effective at a dose of 60-70 µg/kg (an 8 and 2 fold increase in their efficacy, respectively). Therefore, we used DSP as a novel FT adjunct the Streptococcus pneumoniae pleural injury model.
Methods: Pleural injury was induced by intrapleural injection of 1×108cfu of S. pneumoniae. The development of pleural injury was monitored by ultrasonography and pulmonary function tests. Animals were treated with minimally effective doses (MID; 0.5 mg/kg) of sctPA and scuPA. Animals were euthanized at 24h after FT and the outcomes were assessed postmortem. LC/MS/MS mass spectrometry was employed to monitor DSP in samples of pleural fluid collected at 10, 20 40 min and at 24h after treatment.
Results: DSP (2 mg/kg) did not increase the efficacy of a MID of scuPA when treating acute S. pneumoniae empyema. In contrast, there was a trend towards improving therapeutic outcomes after treatment with a MID of sctPA (0. 5 mg/kg). A two-fold increase in the dose of DSP (4 mg/kg) further improved therapeutic outcomes with a MID of sctPA. An increase in the efficacy of FT with a MID of sctPA by DSP was accompanied by an improvement in pulmonary function - a decrease in resistance and increase in compliance. However, the combination of 4 mg/kg of DSP with one half of a MID of sctPA (0.25 mg/kg) was ineffective. DSP was detected in pleural fluids collected at 0-40 min by LC/MS/MS mass spectrometry.
Conclusions: The DSP, which drastically improved the efficacy of FT with scuPA and sctPA in chemically-induced pleural injury, was ineffective with a MID of scuPA and only moderately effective with a MID of sctPA in S. pneumoniae empyema. Thus, different molecular mechanisms of fibrinolysis likely govern the effects of DSP on FT in chemical and infectious pleural injury.
|
Home
|
Inbox
|
Search
|