An anti-inflammatory property of aprotinin detected at the level of leukocyte extravasation

Background: Aprotinin is a serine protease inhibitor used extensively in ca rdiac operations to reduce postoperative bleeding. It has also been used in trials aimed at reducing the systemic inflammatory response to cardiopulmo nary bypass. It remains unclear whether the anti-inflammatory action of apr otinin is related to its general ability to suppress leukocyte activation o r whether aprotinin can exercise effects during the leukocyte-endothelial c ell adhesion cascade. Methods: We used intravital microscopy to study the 3 main stages of the ad hesion cascade (leukocyte rolling, firm adhesion, and extravasation) within the mesenteric microcirculation of rats. This in vivo technique allows leu kocyte recruitment to be viewed directly through the transparent mesentery of anesthetized animals, Results: Aprotinin, given by continuous infusion at a clinically relevant d ose, exerted no effect on the rolling or firm adhesion responses toward loc al chemoattractant N-formyl-methyl-leucyl-phenylalanine but significantly i nhibited extravasation of leukocytes (73% at 40 minutes, P =.03) into surro unding tissues. In parallel in vitro experiments, aprotinin (used at 200, 8 00, and 1600 kIU/mL) dose dependently inhibited neutrophil transmigration t hrough cultured endothelial cells in response to 3 different chemoattractan ts: N-formyl-methyl-leucyl-phenylalanine (P <.001 at 800 and 1600 kIU/mL), interleukin 8 (P <.05 at 200 kIU/mL and P <.001 at 800 and 1600 kIU/mL), an d platelet-activating factor (P <.05 at 1600 kIU/mL), Conclusions: Our studies have therefore revealed a novel anti-inflammatory mechanism of aprotinin operating at the level of leukocyte extravasation. T hese findings may be relevant in the prevention of systemic inflammation af ter cardiopulmonary bypass through the use of protease inhibitors.