P‐Selectin Glycoprotein Ligand‐1 (rPSGL‐Ig)‐Mediated Blockade of CD62 Selectin Molecules Protects Rat Steatotic Liver Grafts from Ischemia/Reperfusion Injury

Abstract

We examined the effects of early blockade of CD62 selectin‐mediated adhesive interactions in steatotic rat liver models of ex vivo cold ischemia followed by reperfusion or transplantation by administration of P‐selectin glycoprotein ligand‐1 (rPSGL‐Ig). In the model of cold ischemia/reperfusion, livers pretreated ex vivo with rPSGL‐Ig at harvesting from obese Zucker rats showed significantly decreased portal resistance, increased bile production, and diminished hepatic endothelial neutrophil infiltration, as compared with untreated controls. Pretreatment of fatty livers with rPSGL‐Ig prior to transplantation extended the survival of lean Zucker rat recipients from 40% to 90%. This effect correlated with significantly improved liver function, depressed neutrophil activity, and decreased histologic features of hepatocyte injury. Intragraft expression of CD62 P‐selectin was similar in both recipient groups. rPSGL‐Ig treatment decreased intragraft infiltration by CD3/CD25 cells, diminished expression of pro‐inflammatory TNFα, IL‐6, iNOS, IL‐2 and IFN‐γ, without significantly affecting mRNA levels coding for anti‐inflammatory IL‐4. Thus, rPSGL‐Ig blockade of CD62‐mediated adhesive interactions protects against severe ischemia/reperfusion injury suffered otherwise by steatotic rat livers. These findings document the potential utility of rPSGL‐Ig in increasing the transplant donor pool through modulation of marginal steatotic livers.