Novel iron chelator in combination with a P-selectin antagonist prevents ischemia/reperfusion injury in a rat liver model

Background. Hepatic ischemia/reperfusion (I/R) injury is associated with ea rly and late graft failure after Liver transplantation. A major mechanism i s leukocyte adhesion to endothelium followed by release of reactive oxygen intermediates. We examined whether desferriexochelin 772SM (D-Exo), a lipid soluble iron chelator that prevents hydroxyl radical formation, can enhanc e the capacity of recombinant P-selectin glycoprotein ligand immunoglobulin (rPSGL-Ig), a glycoprotein that binds to P-selectin and inhibits neutrophi l adhesion, to protect against I/R injury in an ex vivo rat liver model. Methods. Rat livers were harvested and stored for 6 hr at 4 degreesC in Uni versity of Wisconsin solution and then perfused with oxygenated whole blood for 2 hr, Three groups were studied (n=6 rats/group): an untreated control group; a group that received 0.4 mg/kg rPSGL-Ig intraportally at the time of harvest; and a group that received 0.4 mg/kg rPSGL-Ig plus 1 mu mol D-Ex o intraportally both at the time of harvest and at the onset of reperfusion , Liver portal venous blood flow was assessed during perfusion, and at the end of each experiment, liver samples were collected for blinded histologic al evaluation and biochemical analyses. Results. Livers treated with D-Exo + rPSGL-Ig had significantly higher bloo d flow than livers treated with rPSGL-1Ig alone (P<0.05), and both treatmen t groups had higher blood flow than controls (P<0.001). Production of carbo nyl proteins, a protein oxidation product, was significantly reduced in the D-Exo + rPSGL-1Ig group (P<0.02 vs. controls), but not in the rPSGL-Ig alo ne group. Total reduced glutathione was significantly higher than controls in the D-Exo + rPSGL-Ig group (P<0.001 vs. controls), but not in the rPSGL- Ig alone group, indicating less oxidative stress in the D-Exo-treated group , Production of malondialdehyde, an index of lipid peroxidation, was signif icantly less than controls in both treatment groups (P<0.03). Histopatholog ical findings paralleled these results with Banff's scores of 3.3+/-0.5, 1. 8+/-0.4, and 1.3+/-0.5 in the control, rPSGL-Ig alone, and D-Exo plus rPSGL -Ig groups, resp. Conclusion. rPSCL-Ig provides partial protection against I/R injury to ex v ivo rat livers; however, the addition of D-Exo substantially increases prot ection by reducing oxidative injury. These findings may have clinical relev ance in preventing the consequences of I/R injury after liver transplantati on.