Protection of sinusoidal endothelial cells against storage/reperfusion injury by prostaglandin E2 derived from Kupffer cells.
BACKGROUND
In clinical liver transplants, grafts are frequently exposed to endotoxin (lipopolysaccharide, LPS) before harvest and may be predisposed to dysfunction. Because graft failure is linked to sinusoidal endothelial cell injury after storage/reperfusion, we investigated the effect of donor exposure to LPS on graft survival in relation to sinusoidal endothelial cell injury after storage/reperfusion in rats.


METHODS
Rats were injected with 0.5 mg/kg LPS. In some rats, 20 mg/kg GdCl3 or 5 mg/kg indomethacin was injected before LPS to ablate Kupffer cells and inhibit prostaglandin (PG) synthesis, respectively. Other rats were injected with 100 microg/kg dimethyl PGE2, a stable PGE2 analog. Rat livers were harvested, stored in cold UW solution and transplanted to non-treated rats for determination of survival and liver injury in recipients. Otherwise, after cold storage, the livers were reperfused briefly with physiological buffer containing trypan blue for determination of sinusoidal endothelial cell injury by counting trypan blue-positive nuclei in histological sections.


RESULTS
Donor treatment with LPS increased hepatic PGE2 production before storage and decreased recipient survival, but paradoxically decreased killing of sinusoidal endothelial cells after storage and reperfusion. Pretreatment of donors with GdCl3 or indomethacin prevented the protective preconditioning of sinusoidal endothelial cells by LPS, whereas pretreatment with dimethyl PGE2 protected sinusoidal endothelial cells to the same extent as LPS. Unlike LPS, however, PGE2 attenuated graft injury after liver transplants.


CONCLUSIONS
PGE2 derived from LPS-stimulated Kupffer cells protects sinusoidal endothelial cells against storage/reperfusion injury. Unlike LPS, PGE2 improves graft function after liver transplants. Thus, donor preconditioning with PGE2 may be beneficial in liver transplants.
Arai
M
M
Department of Cell Biology and Anatomy, School of Medicine, University of North Carolina at Chapel Hill, 27599-7090, USA.
Peng
X X
XX
Currin
R T
RT
Thurman
R G
RG
Lemasters
J J
JJ
D000818:Animals; D015232:Dinoprostone / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000166:cytology; D006085:Graft Survival / Q000187:drug effects; D007728:Kupffer Cells / Q000737:chemistry; D008070:Lipopolysaccharides / Q000627:therapeutic use; D008099:Liver / Q000098:blood supply* / Q000166:cytology*; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D009926:Organ Preservation; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*
D008070:Lipopolysaccharides; D015232:Dinoprostone