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J Thorac Cardiovasc Surg 2001;122:123-128
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Effect of aprotinin on endothelial cell activation

From the British Heart Foundation, Cardiac Surgery^a and Cardiovascular Medicine^b Units, Hammersmith Hospital, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom.

Received for publication Aug 30, 2000. Revisions requested Nov 14, 2000; revisions received Dec 4, 2000. Accepted for publication Jan 17, 2001. Address for reprints: R. Clive Landis, PhD, BHF Cardiovascular Medicine Unit at Hammersmith Hospital, National Heart and Lung Institute, Imperial College School of Medicine, Du Cane Rd, London W12 0NN, United Kingdom (E-mail: r.landis{at}ic.ac.uk).

Abstract

Background: Cardiopulmonary bypass surgery is often accompanied by a systemic inflammatory response, which can lead to postoperative complications in high-risk patients. This is mediated in part through a systemic rise in inflammatory 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 endothelium. Here we have focused on whether aprotinin has an effect on endothelial cell activation and adhesion molecule expression in response to tumor necrosis factor–, particularly with reference to whether aprotinin inhibits tumor necrosis factor–stimulated neutrophil transendothelial migration.
Methods and Results: Intercellular adhesion molecule–1, vascular cell adhesion molecule–1, and E-selectin expression was studied in tumor necrosis factor––activated human umbilical vein endothelial cells in the presence of aprotinin at 200, 800, and 1600 kIU/mL. Aprotinin inhibited tumor necrosis factor––stimulated expression of intercellular adhesion molecule–1 (P = .019 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 microvascular endothelial cell line, HMEC-1, which exhibited diminished intercellular adhesion molecule–1 expression in the presence of aprotinin (P = .040 at 800 kIU/mL and P < .001 at 1600 kIU/mL). Aprotinin also significantly inhibited neutrophil transmigration across tumor necrosis factor––activated human umbilical vein endothelial cells (P = .046 at 1600 kIU/mL).
Conclusions: We have demonstrated that aprotinin inhibits intercellular adhesion molecule–1 and vascular cell adhesion molecule–1, but not E-selectin, expression on tumor necrosis factor––activated endothelial cells and that transendothelial migration by neutrophils is also specifically suppressed under these conditions. Our results indicate that endothelial cells can be specifically targeted by aprotinin, therefore adding to our understanding of the anti-inflammatory mechanism of action of aprotinin during cardiopulmonary bypass.

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