*G Asimakopoulos, R Thompson, S Nourshargh, DO Haskard, *CP Ratnatunga, *KM Taylor, RC Landis.

Cardiovascular Medicine and *Cardiothoracic Unit, Imperial College School of Medicine at Hammersmith Hospital, London.

Background: Leukocyte activation, adhesion to endothelial cells and transmigration through the vessel wall are regarded as important factors that can lead to inflammation-related tissue injury. We conducted this study to investigate whether the anti-inflammatory action of aprotinin is related to its general ability to suppress leukocyte activation or whether aprotinin can exercise specific inhibitory effects at particular stages of the adhesive interactions between leukocytes and the vessel wall.

Methods and Results: We investigated the effect of aprotinin on the expression of neutrophil adhesion molecules in peripheral blood of humans (L-selectin and Mac-1) and rats (L-selectin). We found that aprotinin at 800 and 1,600 kiu/ml afforded significant protection from L-selectin shedding in both species induced through the bacterial chemoattractant fMLP. To ask whether alterations in adhesion molecule expression might affect leukocyte recruitment in vivo, we extended our study to an animal inflammatory model using intravital microscopy to visualise leukocyte responses to fMLP directly through the transparent mesenteric tissue of anaesthetised rats. Intravital microscopy revealed that aprotinin, given by continuous infusion at a clinically relevant dose, exerted no effect on leukocyte rolling or firm adhesion to the vessel wall, but significantly inhibited the migration of leukocytes into the surrounding tissue (72.5% inhibition in comparison to control animals at 40 min, P < 0.032).

Conclusions: Aprotinin reduces neutrophil L-selectin shedding and leukocyte extravasation induced by fMLP. These actions may contribute to the anti-inflammatory effects of aprotinin and may provide protection against the systemic inflammatory response.