Sulfo-Lewis(x) diminishes neutrophil infiltration and free radicals with minimal effect on serum cytokines after liver ischemia and reperfusion.
BACKGROUND
Cell adhesion plays a central role in the pathogenesis of neutrophil-induced hepatic injury after ischemia and reperfusion. Sialyl Lewis(x) binds to selectins mediating neutrophil adherence to endothelium, thereby facilitating subsequent migration and tissue damage.


OBJECTIVE
We studied the effect of a novel sulfo-derivative of sialyl Lewis(x), GM-1998, on the liver inflammatory response after ischemia and reperfusion. Specifically, we evaluated its impact on three key inflammatory mediators: neutrophil migration, free radicals, and serum cytokines.


METHODS
Rats were subjected to total hepatic ischemia for 90 min using an extracorporeal portosystemic shunt to avoid splanchnic congestion. GM-1998 was given at a total dose of 20 mg/kg both prior to and after reperfusion. Liver function tests, liver tissue free radicals, and myeloperoxidase (MPO), serum cytokines (IL-1, TNF-alpha), and liver histology were analyzed 4 hr after reperfusion. Additionally, survival was followed for up to 7 days.


RESULTS
Seven-day survival significantly increased from 20% in the control group to 65% in the sulfo-Lewis(x) treated group. Liver function tests and histological damage scores were improved in comparison to controls. We observed significant downregulation of free radicals and neutrophil migration. This compound did not significantly affect serum cytokine levels.


CONCLUSIONS
GM-1998 showed a protective effect in an in vivo model of severe liver ischemia and reperfusion by decreasing tissue free radical levels and selectin-mediated neutrophil migration. This protective effect was also reflected in improved liver function tests and histological response leading to better survival. We confirmed the beneficial effect of neutrophil blockade as a key target to prevent damage after the reperfusion phenomenon by using a glycomimetic sulfo-Lewis(x).
Garcia-Criado
F J
FJ
Department of Surgery, Experimental Surgery, University of Salamanca, Spain.
Palma-Vargas
J M
JM
Valdunciel-Garcia
J J
JJ
Gomez-Alonso
A
A
Srivastava
O
O
Ezrin
A
A
Anderson
M B
MB
Toledo-Pereyra
L H
LH
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D005732:Gangliosides / Q000494:pharmacology*; D007375:Interleukin-1 / Q000097:blood*; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009844:Oligosaccharides / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*; D000080506:Sialyl Lewis X Antigen; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; C107334:GM 1998; D005732:Gangliosides; D007375:Interleukin-1; D009844:Oligosaccharides; D017382:Reactive Oxygen Species; D000080506:Sialyl Lewis X Antigen; D014409:Tumor Necrosis Factor-alpha; C094688:sialyl Lewis(x) ganglioside; D002374:Catalase; D009195:Peroxidase; D013482:Superoxide Dismutase