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, Sial yl Lewis(x) binds to selectins mediating neutrophil adherence to endot helium, thereby facilitating subsequent migration and tissue damage. A im: We studied the effect of a novel sulfo-derivative of sialyl Lewis( x), GM-1998, on the liver inflammatory response after ischemia and rep erfusion, Specifically, we evaluated its impact on three key inflammat ory mediators: neutrophil migration, free radicals, and serum cytokine s, Material and methods: Rats were subjected to total hepatic ischemia for 90 min using an extracorporeal portosystemic shunt to avoid splan chnic congestion, GM-1998 was given at a total dose of 20 mg/kg both p rior to and after reperfusion, Liver function tests, liver tissue free radicals, and myeloperoxidase (MPG), serum cytokines (IL-1, TNF-alpha ), and liver histology were analyzed 4 hr after reperfusion, Additiona lly, survival was followed for up to 7 days, Results: Seven-day surviv al significantly increased from 20% in the control group to 65% in the sulfo-Lewis(x) treated group. Liver function tests and histological d amage scores were improved in comparison to controls. We observed sign ificant downregulation of free radicals and neutrophil migration, This compound did not significantly affect serum cytokine levels, Conclusi ons: GM-1998 showed a protective effect in an in vivo model of severe liver ischemia and reperfusion by decreasing tissue free radical level s and selectin-mediated neutrophil migration, This protective effect w as also reflected in improved liver function tests and histological re sponse leading to better survival, We confirmed the beneficial effect of neutrophil blockade as a key target to prevent damage after the rep erfusion phenomenon by using a glycomimetic sulfo-Lewis(x). (C) 1997 A cademic Press.