These data indicate a new and different protective mechanism for FK506 in regard to its ability to down-regulate free radical levels in livers subjected to severe ischemia and reperfusion. Tacrolimus, also confirmed to be a potent suppressor of the cytokine response, specifically interleukin 1 and tumor necrosis, decreased neutrophil tissue migration as well.

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cytes. One mechanism of accumulation is cell adhesion. Background: Cell adhesion plays a central role in The selectin family of adhesion molecules play a pivotal the pathogenesis of neutrophil-induced hepatic injury role in the leukocyte/endothelial cell events associated after ischemia and reperfusion. Sialyl Lewis x binds to with tissue inflammation and damage following ischselectins mediating neutrophil adherence to endothe-emia and reperfusion (I/R) [1][2][3][4]. Previous in vitro and lium, thereby facilitating subsequent migration and in vivo studies have clearly implicated neutrophil mitissue damage. Aim: We studied the effect of a novel gration as one of the key mechanisms involved in hesulfo-derivative of sialyl Lewis x , GM-1998, on the liver patic I/R injury [5][6][7][8].inflammatory response after ischemia and reperfu-P-and E-selectin, expressed on the activated vassion. Specifically, we evaluated its impact on three key cular endothelium following I/R, mediate neutrophil inflammatory mediators: neutrophil migration, free adhesion at sites of tissue injury and inflammation radicals, and serum cytokines. Material and methods: [9 -12] In this study, we investigated the effect of a glya), and liver histology were analyzed 4 hr after reperfusion. Additionally, survival was followed for up to 7 comimetic [17, 18], novel sulfo-derivative of sialyl days. Results: Seven-day survival significantly in-Lewis x , GM-1998, in an in vivo model of liver I/R. We creased from 20% in the control group to 65% in the hypothesized that this synthetic glycomimetic could sulfo-Lewis x treated group. Liver function tests and compete against the natural sialyl Lewis x ligand for histological damage scores were improved in compari-the selectin receptor, thereby blocking selectin-medison to controls. We observed significant downregula-ated neutrophil adhesion. In addition, we explored tion of free radicals and neutrophil migration. This the effects of GM-1998 on the regulation of two other compound did not significantly affect serum cytokine key inflammatory mediators, free radicals and serum levels. Conclusions: GM-1998 showed a protective ef-cytokines (specifically IL-1 and TNF-a levels), in livfect in an in vivo model of severe liver ischemia and ers subjected to I/R. reperfusion by decreasing tissue free radical levels and selectin-mediated neutrophil migration. This pro-MATERIAL AND METHODS tective effect was also reflected in improved liver function tests and histological response leading to better survival. We confirmed the beneficial effect of neutroOne hundred and fifty male Sprague-Dawley rats (Charles River Breeding Laboratories, Inc., Portage, MI), weighing 250-275 g, were phil blockade as a key target to prevent damage after fasted for 12 hr before surgery and allowed water ad libitum. Rats the reperfusion phenomenon by using a glycomimetic were anesthetized with Ketamine hydrochloride (Ketalar, Parke-

CY-1503 exerts a protective effect in that it able to down-regulate concentrations of free radicals in our rat model. It is a potent inhibitor of neutrophil migration, but has no effect on cytokine concentrations.