Plasminogen-Plasmin System in the Pathogenesis and Treatment of Lung and Pleural Injury
ABSTRACT Lung and pleural injuries are characterized by inflammation, fibrinous transitional matrix deposition, and ultimate scarification. The accumulation of extravascular fibrin is due to concurrently increased local coagulation and decreased fibrinolysis, the latter mainly as a result of increased plasminogen activator inhibitor-1 (PAI-1) expression. Therapeutic targeting of disordered fibrin turnover has long been used for the treatment of pleural disease. Intrapleural fibrinolytic therapy has been found to be variably effective in clinical trials, which likely reflects empiric dosing that does not account for the wide variation in pleural fluid PAI-1 levels in individual patients. The incidence of empyema is increasing, providing a strong rationale to identify more effective, nonsurgical treatment to improve pleural drainage and patient outcomes. Therapeutics designed to resist inhibition by PAI-1 are in development for the treatment of pleural loculation and impaired drainage. The efficacy and safety of these strategies remains to be proven in clinical trial testing. Fibrinolytic therapy administered via the airway has also been proposed for the treatment of acute lung injury, but this approach has not been rigorously validated and is not part of routine clinical management at this time. Challenges to airway delivery of fibrinolysins relate to bioavailability, distribution, and dosing of the interventional agents.
- Seminars in Thrombosis and Hemostasis 06/2013; 39(4):327-328. DOI:10.1055/s-0033-1343616 · 3.69 Impact Factor
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ABSTRACT: Local derangements of fibrin turnover and plasminogen activator inhibitor-1 (PAI-1) have been implicated in the pathogenesis of pleural injury. However, their role in the control of pleural organization has been unclear. We found that a C57Bl/6j mouse model of carbon black-bleomycin (CBB) injury demonstrates pleural organization resulting in pleural rind formation (14 d). In transgenic (Tg) mice overexpressing human PAI-1, intrapleural fibrin deposition was increased, but visceral pleural thickness, lung volumes and compliance were comparable to WT. CBB-injury in PAI-1-/- mice significantly increased visceral pleural thickness (P<0.001) and lung compliance (P<0.01) while decreasing lung volumes. Collagen, α-SMA, and tissue factor were increased in the thickened visceral pleura of PAI-1-/- mice. Colocalization of α-SMA and calretinin within pleural mesothelial cells (PMCs) was increased in CBB injured PAI-1-/- mice. Thrombin, FXa, plasmin and urokinase induced meso-mesenchymal transition (MesoMT), TF expression and activity in primary human PMCs. In PAI-1-/- mice, D-dimer and thrombin-antithrombin complex concentrations were increased in pleural lavage fluids. The results demonstrate that PAI-1 regulates CBB-induced pleural injury severity via unrestricted fibrinolysis and cross-talk with coagulation proteases. While overexpression of PAI-1 augments intrapleural fibrin deposition, PAI-1 deficiency promotes profibrogenic alterations of the mesothelium that exacerbate pleural organization and lung restriction.American Journal of Respiratory Cell and Molecular Biology 09/2013; 50(2). DOI:10.1165/rcmb.2013-0300OC · 4.11 Impact Factor