Small-molecule selectin inhibitor protects against liver inflammatory response after ischemia and reperfusion

• Published in: Journal of the American College of Surgeons Vol. 185; no. 4; pp. 365 - 372
• Main Authors: Palma-Vargas, J.M, Toledo-Pereyra, Luis, Dean, Richard E, Harkema, James M, Dixon, Richard A.F, Kogan, Timothy P
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.1997; Elsevier Science; American College of Surgeons
• Subjects: Animals; Antibodies, Monoclonal; Biological and medical sciences; Biphenyl Compounds - pharmacology; Disease Models, Animal; Gastroenterology. Liver. Pancreas. Abdomen; Inflammation; Liver - blood supply; Liver - immunology; Liver - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Mannose - analogs & derivatives; Mannosides - pharmacology; Medical sciences; Necrosis; Neutrophil Activation; Other diseases. Semiology; Peroxidase - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion Injury - immunology; Reperfusion Injury - prevention & control; Selectins - drug effects; Selectins - metabolism; Animal model; Pathophysiology; Rat; E Selectin; Treatment efficiency; Liver; Rodentia; Cardiovascular disease; Hepatic disease; Exploration; Inflammation; L Selectin; P Selectin; Vertebrata; Mammalia; Reperfusion; Ischemia; Inhibitor; Neutrophil
• ISSN: 1072-7515; 1879-1190
• DOI: 10.1016/S1072-7515(01)00943-7

Background: The selectin family of adhesion molecules plays a key role in the neutrophil-mediated injury observed after ischemia and reperfusion. In our study, we investigated the effects of TBC-1269, a novel small-molecule, nonoligosaccharide inhibitor of P-, E-, and L-selectin binding, in the liver inflammatory response after 90 minutes of warm ischemia. Study Design: Total liver ischemia was produced in Sprague-Dawley 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 treated groups receiving TBC-1269 at a dose of 25 mg/Kg at different times of administration: 15 minutes before reperfusion (group 3), at reperfusion (group 4), and 15 minutes after reperfusion (group 5). The following indices were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology. Results: TBC-1269 treated groups experienced a significant increase in survival compared with controls. Best overall survival, 70%, was observed when TBC-1269 (Texas Biotechnology Corporation, Houston, TX) was administered 15 minutes before reperfusion (p < 0.05). This group also showed a marked decrease (p < 0.05) in liver enzyme levels at 6 hours after reperfusion. Neutrophil migration was also significantly ameliorated (81%), as reflected by decreased myeloperoxidase levels. We observed improved histologic damage scores in the treated group compared with controls (p < 0.05). Conclusions: A small-molecule selectin inhibitor (TBC-1269) had a protective effect in livers subjected to 90 minutes of warm hepatic ischemia and 6 hours of reperfusion by decreasing neutrophil infiltration, migration and subsequent tissue damage. The best protective effect was achieved when the compound was administered 15 minutes before reperfusion. These findings offer a new therapeutic alternative for protection against ischemia and reperfusion injury.