SMALL-MOLECULE SELECTIN INHIBITOR PROTECTS AGAINST LIVER INFLAMMATORYRESPONSE AFTER ISCHEMIA AND REPERFUSION

Background: The selectin family of adhesion molecules plays a key role in the neutrophil-mediated injury observed after ischemia and reperfu sion, In our study, we investigated the effects of TBC-1269, a novel s mall-molecule, nonoligosaccharide inhibitor of P-, E-, and L-selectin binding, in the liver inflammatory response after 90 minutes of warm i schemia, Study Design: Total liver ischemia was produced in Sprague-Da wley rats for 90 minutes using an extracorporeal portosystemic shunt, The animals were divided into five groups including: the sham (group 1 ), ischemic control (group 2) receiving only the vehicle, and the trea ted groups receiving TBC-1269 at a dose of 25 mg/kg at different times of administration: 15 minutes before reperfusion (group 3), at reperf usion (group;4), and 15 minutes after reperfusion (group 5), The follo wing indices were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liv er histology, Results: TBC-1269 treated groups experienced a significa nt increase in survival compared with controls, Best overall survival, 70%, was observed when TBC-1269 (Texas Biotechnology Corporation, Hou ston, TX) was administered 15 minutes before reperfusion (p < 0.05), T his group also showed a marked decrease (p < 0.05) in liver enzyme lev els at 6 hours after reperfusion, Neutrophil migration was also signif icantly ameliorated (81%), as reflected by decreased myeloperoxidase l evels, We observed improved histologic damage scores in the treated gr oup compared with controls (p < 0.05), Conclusions: A small-molecule s electin inhibitor (TBC-1269) had a protective effect in livers subject ed to 90 minutes of warm hepatic ischemia and 6 hours of reperfusion b y decreasing neutrophil infiltration, migration and subsequent tissue damage, The best protective effect was achieved when the compound was administered 15 minutes before reperfusion, These finding offer a new therapeutic alternative for protection against ischemia and reperfusio n injury, (C) 1997 by the American College of Surgeons.