UROKINASE DOES NOT UP-REGULATE THE VASCULAR ENDOTHELIAL CELL-MEDIATEDINFLAMMATORY RESPONSE

Purpose: Urokinase is used clinically for thrombolysis, but Little is known of its direct effect on vascular endothelial cells. The followin g experiments were preformed to assess the in vitro effects of urokina se on vascular endothelial cell growth, adhesion molecule expression, and interaction with lymphocytes, polymorphonuclear leukocytes, and pl atelets. Methods: Commercially available human umbilical vein endothel ial cells (HUVEC) were cultured with varying concentrations of urokina se (0 to 10,000 IU/ml) (clinical dosage, less than or equal to 500 IU/ ml). HUVEC viability was determined from 1 to 4 days. HUVECs were incu bated with urokinase (0 to 2000 IU/ml) from 4 to 72 hours. Adherence o f (51)-chromium-labeled polymorphonuclear leukocytes, platelets, or ly mphocytes was then quantitated. In separate experiments HUVEC adhesion molecule expression (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or endothelial leukocyte adhesion molecule-1) wa s determined by flow cytometry. Results:There was a decrease of HUVEC viability at suprapharmacologic urokinase concentrations of greater th an or equal to 2000 IU/ml compared with nontreated control samples (0 IU/ml, 73% +/- 2%, 2000 IU/ml, 60.5% +/- 1.9%, P < 0.05) presumably be cause of drug toxicity. There was no significantly increased polymorph onuclear leukocyte, lymphocyte, or platelet adhesion to urokinase-trea ted HUVEC monolayers at any time point. This was also true for each ad hesion molecule tested. Conclusions: Urokinase at clinically relevant concentrations (less than or equal to 500 IU/ml) did not affect endoth elial cell viability or growth, nor did it upregulate adhesion molecul e expression or cellular adhesion associated with the local vascular i nflammatory response. It is therefore implied that the use of urokinas e in vivo similarly would not initiate the vascular inflammatory respo nse.