An anti-inflammatory property of aprotinin detected at the level of leukocyte extravasation.
BACKGROUND
Aprotinin is a serine protease inhibitor used extensively in cardiac operations to reduce postoperative bleeding. It has also been used in trials aimed at reducing the systemic inflammatory response to cardiopulmonary bypass. It remains unclear whether the anti-inflammatory action of aprotinin is related to its general ability to suppress leukocyte activation or whether aprotinin can exercise effects during the leukocyte-endothelial cell adhesion cascade.


METHODS
We used intravital microscopy to study the 3 main stages of the adhesion cascade (leukocyte rolling, firm adhesion, and extravasation) within the mesenteric microcirculation of rats. This in vivo technique allows leukocyte recruitment to be viewed directly through the transparent mesentery of anesthetized animals.


RESULTS
Aprotinin, given by continuous infusion at a clinically relevant dose, exerted no effect on the rolling or firm adhesion responses toward local chemoattractant N -formyl-methyl-leucyl-phenylalanine but significantly inhibited extravasation of leukocytes (73% at 40 minutes, P =.04) into surrounding tissues. In parallel in vitro experiments, aprotinin (used at 200, 800, and 1600 kIU/mL) dose dependently inhibited neutrophil transmigration through cultured endothelial cells in response to 3 different chemoattractants: 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), and 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. These findings may be relevant in the prevention of systemic inflammation after cardiopulmonary bypass through the use of protease inhibitors.
British Heart Foundation Cardiothoracic Unit and the Cardiovascular Medicine Unit at Hammersmith Hospital, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom.
G
G
Asimakopoulos
R
R
Thompson
S
S
Nourshargh
E A
EA
Lidington
J C
JC
Mason
C P
CP
Ratnatunga
D O
DO
Haskard
K M
KM
Taylor
R C
RC
Landis
D000704:Analysis of Variance; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008833:Microcirculation; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013152:Splanchnic Circulation; D018709:Statistics, Nonparametric
D015842:Serine Proteinase Inhibitors; D009240:N-Formylmethionine Leucyl-Phenylalanine; D007611:Aprotinin; D009195:Peroxidase