Dual role of Kupffer cell activation and endothelial cell damage in reperfusion injury to livers stored for transplantation surgery

Abstract

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.

Graft preconditioning with low-dose tacrolimus (FK506) and nitric oxide inhibitor aminoguanidine (AGH) reduces ischemia/reperfusion injury after liver transplantation in the rat

“…Altough the functional and histologic improvement resulting from only AGH (group III) preconditioning was not as dramatic as for dual preconditioning (group IV), our study shows that low-dose FK506 in combination with AGH (group IV) also can be used to induce ischemic tolerance. These histopathological findings were consistent with the results of previous studies, showing rapid repopulation of sinusoidal endothelial cells in an allogenic model of LTx from the second day on after an I/R injury (Lemasters, 1995;Stolz, 2007). In the present study, we provide strong evidence that a dual pharmacological preconditioning has a preventive effect against I/R injury in rat livers after transplantation.…”

The utility of marginal donors in liver transplantation

“…The energy stores of the liver (e.g., ATP, glycogen) are depleted, severely compromising hepatocyte function. 41,70 Furthermore, morphologic changes to the endothelial cells are observed, resulting in an endothelin/nitric oxide imbalance during the reperfusion period, which has been correlated with decreased liver blood flow. 64,66,71 Steatotic livers have been shown to be more susceptible to IR injury after transplantation.…”

“…40 Additional factors contributing to the poor outcomes of fatty livers after transplantation may include Kupffer cell dysfunction, increased leukocyte adhesion, more vigorous lipid peroxidation, and ischemic necrosis of endothelial cells. 41 Steatotic livers have been associated with increased primary nonfunction 35,42,43 and initial poor graft function, although recoverable within the first week after liver transplantation. 44 Grafts that have more than 60% fat content should not be used, unless there is an urgent situation requiring them to be used as a bridge.…”

Long-term cold liver storage induces endothelin-1 release and a time-dependent increase in portal pressure at reperfusion in the rat

“…40 Cold storage is known to lead to large changes in vascular permeability, because the integrity of the hepatic endothelium is the primary target of injury in cold ischemia. 41 Thus, in cold ischemia, liver surface fluorescence will also reflect the extravasation of FITC-dextran to the space of Disse due to increased sinusoidal permeability. Although the method could not provide a mechanistic explanation of the phenomenon of elevated portal pressure, it presents an approach with which to visualize the microcirculatory disturbances induced by cold storage.…”