P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury.
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 TNFalpha, IL-6, iNOS, IL-2 and IFN-gamma, 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.
The Dumont-UCLA Transplant Center, Department of Surgery, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Farin
F
Amersi
Douglas G
DG
Farmer
Gray D
GD
Shaw
Hirohisa
H
Kato
Ana J
AJ
Coito
Fady
F
Kaldas
Delai
D
Zhao
Charles R
CR
Lassman
Judy
J
Melinek
Jeffrey
J
Ma
Hans-Dieter
HD
Volk
Jerzy W
JW
Kupiec-Weglinski
Ronald W
RW
Busuttil
D000818:Animals; D016207:Cytokines / Q000235:genetics; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009926:Organ Preservation / Q000379:methods*; D019007:P-Selectin / Q000494:pharmacology* / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000517:prevention & control*; D013231:Steatitis / Q000209:etiology / Q000517:prevention & control*; D013997:Time Factors; D014184:Transplantation, Homologous
D016207:Cytokines; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D009195:Peroxidase