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 Streptococcus pneumoniae-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.

A Novel Rabbit Model of Retained Hemothorax with Pleural Organization.

Retained hemothorax (RH) is a commonly encountered and potentially severe complication of intrapleural bleeding that can organize with lung restriction. Early surgical intervention and intrapleural fibrinolytic therapy have been advocated. However, the lack of a reliable, cost-effective model amenable to interventional testing has hampered our understanding of the role of pharmacological interventions in RH management. Here, we report the development of a new RH model in rabbits. RH was induced by sequential administration of up to three doses of recalcified citrated homologous rabbit donor blood plus thrombin via a chest tube. RH at 4, 7, and 10 days post-induction (RH4, RH7, and RH10, respectively) was characterized by clot retention, intrapleural organization, and increased pleural rind, similar to that of clinical RH. Clinical imaging techniques such as ultrasonography and computed tomography (CT) revealed the dynamic formation and resorption of intrapleural clots over time and the resulting lung restriction. RH7 and RH10 were evaluated in young (3 mo) animals of both sexes. The RH7 recapitulated the most clinically relevant RH attributes; therefore, we used this model further to evaluate the effect of age on RH development. Sanguineous pleural fluids (PFs) in the model were generally small and variably detected among different models. The rabbit model PFs exhibited a proinflammatory response reminiscent of human hemothorax PFs. Overall, RH7 results in the consistent formation of durable intrapleural clots, pleural adhesions, pleural thickening, and lung restriction. Protracted chest tube placement over 7 d was achieved, enabling direct intrapleural access for sampling and treatment. The model, particularly RH7, is amenable to testing new intrapleural pharmacologic interventions, including iterations of currently used empirically dosed agents or new candidates designed to safely and more effectively clear RH.