Effect of aprotinin on endothelial cell activation

Background: Cardiopulmonary bypass surgery is often accompanied by a system ic inflammatory response, which can lead to postoperative complications in high-risk patients. This is mediated in part through a systemic rise in inf lammatory cytokine levels and the sequestration of leukocytes within organs . Aprotinin has previously been shown to exert an anti-inflammatory effect by preventing the capacity of leukocytes to transmigrate through vascular e ndothelium. Here we have focused on whether aprotinin has an effect on endo thelial cell activation and adhesion molecule expression in response to tum or necrosis factor-alpha, particularly with reference to whether aprotinin inhibits tumor necrosis factor-stimulated neutrophil transendothelial migra tion. Methods and Results: Intercellular adhesion molecule-1, vascular cell adhes ion molecule-1, and E-selectin expression was studied in tumor necrosis fac tor-cl-activated human umbilical vein endothelial cells in the presence of aprotinin at 200, 800, and 1600 kIU/mL. Aprotinin inhibited tumor necrosis factor-a-stimulated expression of intercellular adhesion molecule-1 (P = .0 19 at 1600 kIU/mL) and vascular cell adhesion molecule-1 (P = .003 at 1600 kIU/mL) but not E-selectin. Similar results were obtained in the dermal mic rovascular endothelial cell line, HMEC-1, which exhibited diminished interc ellular adhesion molecule-1 expression in the presence of aprotinin (P = .0 40 at 800 kIU/mL, and P < .001 at 1600 kIU/mL). Aprotinin also significantl y inhibited neutrophil transmigration across tumor necrosis factor-alpha -a ctivated human umbilical vein endothelial cells (P = .046 at 1600 kIU/mL). Conclusions: We have demonstrated that aprotinin inhibits intercellular adh esion molecule-1 and vascular cell adhesion molecule-1, but not E-selectin, expression on tumor necrosis factor-alpha -activated endothelial cells and that transendothelial migration by neutrophils is also specifically suppre ssed under these conditions. Our results indicate that endothelial cells ca n be specifically targeted by aprotinin, therefore adding to our understand ing of the anti-inflammatory mechanism of action of aprotinin during cardio pulmonary bypass.