Role of enzymes mediating thrombosis and thrombolysis in lung disease

Abstract

Enzymes of the blood coagulation and fibrinolytic cascades are prominent in both the vascular and alveolar compartments of the human lung. Important differences exist in the regulation of these enzyme activities between the vascular and the alveolar compartments, suggesting different functions of similar enzymes in the two compartments. In the vascular bed, endothelial cells provide a nonthrombogenic lining layer and release small amounts of tissue plasminogen activator into the circulation, maintaining patency of the vascular bed, whereas the alveolar epithelial surface is replete with active enzymes of the extrinsic pathway of coagulation as well as urokinase. The alveolar surface seems primed to localize and degrade any fibrin that has leaked into alveoli during hemorrhagic states. In addition, parenchymal lung cells such as resident macrophages are coated with urokinase, providing a mechanism for cellular migration and ongoing extracellular matrix metabolism. Amplification of the PA/plasmin system in the lung during chronic inflammation, eg, cigarette smoking, could accelerate connective tissue breakdown. Recent evidence indicates that in acute inflammation there is an enhancement of mediators of coagulation and suppression of fibrinolysis. These observations may partly explain prior pathologic observations regarding the deposition of hyaline membranes and persistence of alveolar fibrin/fibronectin deposits that may be stimulants for alveolar fibrosis. The assembly of clotting components on the surface of macrophages and the integral involvement of macrophages with fibrin deposits in the lung are likely mechanisms for macrophage immobilization and focal accumulation important to local clearance, host defense, effective chemotactic signalling, and possibly proliferation since thrombin has mitogenic properties for other lung cells. Newer methods focusing on the biology and biochemistry of the pulmonary architecture and its cellular components should further elucidate the importance of these pathways and suggest new therapeutic options.