In rat models of liver preservation, the primary event leading to liver graft failure after cold storage is a
reperfusion injury causing damage to sinusoidal endothelial cells and activation of Kupffer cells (KC). After storage for longer than 16 h in University of Wisconsin
solution, reperfusion induces rapid endothelial cell killing. Kupffer cell activation also occurs as indicated by cell surface ruffling, degranulation, release of hydrolytic
enzymes, generation of
oxygen radicals, and increased phagocytosis. Down-regulation of KC activity with
nisoldipine or
pentoxifylline improves graft survival. Moreover, pretreatment of donors with small amounts of
endotoxin to activate KC causes a drastic reduction of graft survival. Together, KC activation and endothelial damage cause marked microcirculatory disturbances after
transplantation characterized by reduced and uneven blood flow and increased leucocyte and platelet adhesion. Such events culminate in
inflammation,
necrosis and fulminant graft failure. Modification of reperfusion conditions can reduce the extent of injury. In particular,
flushing livers with
Carolina rinse solution (CRS) at the end of storage reduces endothelial cell killing, suppresses KC activation, improves the microcirculation, and increases graft survival. Active ingredients in CRS include
antioxidants (
allopurinol,
desferrioxamine and
glutathione),
adenosine and slightly acidic pH (6.5). Other potentially important ingredients are
nicardipine, a
calcium channel blocker, and
fructose,
glucose and
insulin to promote glycolysis. The cytoprotective
amino acid,
glycine, further improves the performance of
Carolina rinse solution. Reperfusion-induced changes to nonparenchymal cells play an essential role in damage to livers preserved for
transplantation surgery. Understanding the role of sinusoidal endothelial cells and KC in this injury has led to promising new strategies to prolong organ storage and reduce graft failure.