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A3953 - Fibrinolytic Therapy for Infectious and Chemically-Induced Acute Pleural Injury in Rabbits: Differential Efficacy of sctPA and scuPA
Author Block: G. Florova1, A. Azghani2, A. Buchanan3, M. Chamiso1, R. Girard1, K. Sarva1, A. Tvinnereim1, K. Koenig1, S. Idell1, A. Komissarov1; 1Cellular and Molecular Biology, University 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.
Rationale: Intrapleural fibrinolytic therapy (IPFT) is a well-accepted, conservative approach to treatment of loculated pleural processes. While it is acknowledged as effective for treatment of pediatric patients, there is still controversy regarding the efficacy of IPFT in adults. A contributing factor is a lack of understanding of the molecular mechanisms of intrapleural fibrinolysis, which limits rational approaches to treatment. We therefore compared the efficacy of single chain (sc) urokinase (scuPA) and tissue (sctPA) plasminogen activators for treatment of chemical (tetracycline-induced) and infectious (Streptococcus pneumoniae) organizing pleural injury in rabbits.
Methods: Chemical or infectious pleural injury was induced with intrapleural injection of tetracycline or 1×108cfu of S. pneumoniae (EMP), respectively. The development and progression of pleural injury was monitored using ultrasonography and pulmonary function tests (PFTs). PFTs were done using the flexiVent system (SCIREQ Inc., Montreal, Canada). Animals were treated with different once-daily doses of plasminogen activators over a period of 48-72h after injury and euthanized 24h afterwards. The efficacy of treatment was assessed postmortem using Gross Lung Injury Scores.
Results: The minimal effective dose (MED) of sctPA (0.145 mg/kg) identified for TCN-induced pleural injury was ineffective in S. pneumoniae-induced empyema. Levels of the plasminogen activator inhibitor 1 (PAI-1) were higher in EMP. The MED for scuPA (0.5 mg/kg) was partially effective and, thus, was identified as the maximal ineffective dose (MID) for treatment of EMP. Increasing the dose of sctPA to 0.5 mg/kg resulted in an efficacy comparable to that of the MID of scuPA. The observed difference in efficacy of MID of fibrinolysins, while not statistically significant, could reflect the 20% higher molar dose of scuPA compared to that of sctPA. Pulmonary function tests in EMP rabbits treated with the MID of intrapleural fibrinolysins showed decreased resistance, and increased compliance compared to PBS treated animals.
Conclusions: scuPA and tPA demonstrate different efficacies in acute chemically-induced and infectious pleural injury in rabbits. Profound inhibition of the PAs in EMP fluids was largely attributable to increased PAI-1. These observations justify the use of MIDs of 0.5 mg/kg of either scuPA or sctPA for further development of new interventions such as PAI-1-targeted IPFT in rabbits with S. pneumonia acute-to-chronic EMP, which closely recapitulates disease progression in humans.