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.
Rationale: Pleural empyema is increasing in frequency and is associated with a high mortality rate (>20%) in patients older than 65 years. Progression to an advanced stage results in multi-loculated collections in the pleural space with pleural thickening (up to 10 mm). While pleural thickening in humans is an indication for surgery, a significant cohort of older patients (>30%) have contraindications due to comorbidities. Plasminogen activator inhibitor 1 (PAI-1) targeted fibrinolytic therapy (PAI-1-TFT) allows for an up to 8-fold decrease in the bolus dose of single chain (sc) tissue plasminogen activator (sctPA) that cleared pleural loculation in acute empyema in rabbits [1]. We therefore hypothesized that PAI-1-TFT with anti-PAI-1 monoclonal antibodies (mAbs) could decrease pleural thickening associated with empyema. Methods: Acute (3d) Streptococcus pneumoniae-induced empyema in rabbits was treated with an ineffective dose (0.5 mg/kg) of sctPA or urokinase (scuPA) in combination with two mAbs, MA-33H1F7 and MA-8H9D4 (0.5-1.0 mg/kg). The outcomes were assessed at 24h by ultrasonography, computed tomography, histology, and a multitude of biochemical methods. PAI-1-TFT was considered successful if the Gross Lung Injury Score (GLIS) was ≤10 [1]. Results: At 1.0 mg/kg, mAbs converted an ineffective dose of sctPA (0.5 mg/kg) into an effective one (GLIS≤10, n=6). Effective PAI-1-TFT with sctPA also resulted in a statistically significant (p<0.05) decrease in pleural thickening, when compared to animals treated with mAbs (n=2) or IgG (n=2) alone or IgG in combination with sctPA (n=4). Pleural thickening in a group of animals with acute empyema treated with a combination of scuPA (0.5 mg/kg) and mAbs (0.5 mg/kg) was also decreased. In contrast, PAI-1-TFT with a small Docking Site Peptide decreased the effective dose of sctPA by 8-fold but not pleural thickening [1]. No bleeding complications were observed. Conclusions: While bolus injection of mAb based PAI-1-TFT resulted in a 4-fold increase in the efficacy of sctPA only, pleural thickening was decreased after treatment with both sctPA (p<0.05) and scuPA. Thus, mAb-based PAI-1-TFT represents an innovative approach for treatment of empyema and pleural thickening in patients with contraindications to surgical intervention.
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