THE USE OF CULTURED HUMAN ENDOTHELIAL-CELLS AND HEPATOCYTES AS AN INVITRO MODEL SYSTEM TO STUDY MODULATION OF ENDOGENOUS FIBRINOLYSIS

Tissue-type plasminogen activator (t-PA) plays a pivotal role in the onset of fibrinolysis. Regulation of t-PA activity in the bloodstream occurs at various levels, including release from the endothelium and, to some extent, interaction with a specific inhibitor, PAI-1. Modulation of the fibrinolytic capacity in plasma (endogenous fibrinolysis) would be a powerful means in preventing thrombosis. This paper describes the use of cultured human endothelial cells and hepatocytes as in vitro model systems to study regulation of t-PA and PAI-1 synthesis. Evidence is provided that these models represent useful alternatives for the use of experimental animals in finding compounds that might stimulate endogenous fibrinolysis in humans. These in vitro systems allow detailed studies of regulatory mechanisms, and it is shown that the t-PA synthesizing capacity of endothelial cells is only partially exploited, suggesting that stimulation of endogenous fibrinolysis is feasible. Also, some progress has been made in developing an in vitro system for studying the acute, i.e. within minutes, release of t-PA from endothelial cells and the state of the art of this model is discussed. © 1990.