Sialyl Lewis(x) analog improves liver function by decreasing neutrophil migration after hemorrhagic shock.
BACKGROUND
Little is known about the changes in the hepatic microcirculation and the leukocyte-endothelial adhesion processes during the early reperfusion period after resuscitation in hemorrhagic shock. P-selectin and its natural ligand Sialyl Lewis(x) (SLe(x)) are involved in the early stages of reperfusion events leading to neutrophil migration. Therefore, the aim of this study was to investigate the effect of the administration of CY-1503 [corrected], a synthetic SLe(x) analog, in the liver inflammatory response and neutrophil migration after hemorrhagic shock.


METHODS
Rats, each weighing 275 to 300 grams, were subjected to 60 minutes of pressure controlled hemorrhagic shock. After this period, animals were resuscitated according to the following protocol: shed blood was reinfused to equal 50% of the total volume bled, and the other 50% was replaced with 3x volume of Ringer's lactated solution. Animals were divided into sham and two study groups to receive vehicle (controls) and CY-1503 [corrected] (10 mg/kg intravenously) diluted in 1 mL of normal saline 45 minutes after initiating hemorrhagic shock. The following parameters were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology.


RESULTS
Survival was significantly increased from 48% in the controls to 90% in the CY-1503 [corrected] treated group. Animals treated with the SLe(x) analog showed significantly better mean arterial blood pressure after 15 minutes after resuscitation. Also, the treated group showed a marked decrease in liver enzymes levels at 5 minutes and 4 hours after reperfusion. Neutrophil migration was significantly ameliorated as reflected by decreased myeloperoxidase levels in the SLe(x) analog treated group. Furthermore, we observed improved histologic damage scores in the treated group when compared with controls.


CONCLUSIONS
The SLe(x) analog, CY-1503 [corrected], had a protective effect in ischemic livers by decreasing neutrophil migration after hemorrhagic shock and resuscitation. This protective effect also resulted in improved survival and mean arterial blood pressure after resuscitation.
Rubio-Avilla
J
J
The Surgical Research Institute and Trauma Division at Borgess Medical Center, Kalamazoo, Michigan 49001, USA.
Palma-Vargas
J M
JM
Collins
J T
JT
Smejkal
R
R
McLaren
J
J
Phillips
L M
LM
Toledo-Pereyra
L H
LH
D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007249:Inflammation; D008099:Liver / Q000187:drug effects* / Q000276:immunology*; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects*; D009844:Oligosaccharides / Q000627:therapeutic use*; D019007:P-Selectin / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000276:immunology*; D000080506:Sialyl Lewis X Antigen; D016019:Survival Analysis
C108076:CY 1747; D009844:Oligosaccharides; D019007:P-Selectin; D000080506:Sialyl Lewis X Antigen