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


METHODS
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.
Palma-Vargas
J M
JM
Surgical Research Institute at Borgess Medical Center, Kalamazoo, MI 49001, USA.
Toledo-Pereyra
L
L
Dean
R E
RE
Harkema
J M
JM
Dixon
R A
RA
Kogan
T P
TP
D000818:Animals; D000911:Antibodies, Monoclonal; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D007249:Inflammation; D008099:Liver / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000494:pharmacology*; D009336:Necrosis; D018375:Neutrophil Activation; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology* / Q000517:prevention & control*; D019087:Selectins / Q000187:drug effects* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001713:Biphenyl Compounds; D008362:Mannosides; D019087:Selectins; C108700:bimosiamose disodium; D009195:Peroxidase; D008358:Mannose