INHIBITING THE INHIBITOR: WOULD TARGETING PAI-1 RESULT IN A LOW-DOSE, WELL-TOLERATED TREATMENT OF EMPYEMA?

The incidence of empyema has continued to rise over the past several decades, and mortality rates remain up to 20-27% among patients >65 years old with comorbidities. Up to 30% of adult patients with empyema are poor candidates for both surgical treatment and conventional fibrinolytic therapy. Plasminogen activator inhibitor 1 (PAI-1) inhibits fibrinolysis, promoting pleural fibrosis and lung restriction. We hypothesized that targeting PAI-1 would result in a low-dose pharmacological treatment for empyema, improving patient survival. This hypothesis was tested in rabbit models of chemically-induced and Streptococcus pneumoniae infectious pleural injury. Anti-PAI-1 monoclonal antibodies (mAbs) and a short Docking Site Peptide (DSP), which affect the PAI-1 mechanism differently, were first tested in a rabbit model of chemically-induced pleural injury. Modulating different steps of the PAI-1 mechanism resulted in an up to eight-fold increase in the efficacy of exogenous fibrinolysins. DSP, subsequently tested in a rabbit model of empyema, increased the efficacy of sctPA in both early- and advanced-stage empyema by at least eight and four-fold, respectively. While small-molecule PAI-1 inhibitors are under investigation, there is currently no FDA-approved PAI-1-targeted treatment. We believe that DSP and phage-display selected peptides that compete with mAbs for PAI-1 will be well-tolerated, tractable in clinical settings, and address both pleural fibrosis and thickening with minimal off-target effects. The results support our hypothesis and objective to develop a novel, cost-effective, low-dose pharmacological intervention for empyema suitable for patients who are at elevated risk for surgery or conventional fibrinolytic therapy.