Cold-induced apoptosis of rat liver cells in University of Wisconsin solution: the central role of chelatable iron.
Although University of Wisconsin (UW) solution aims at the prevention of cold-induced cell injury, it failed to protect against cold-induced apoptosis of hepatocytes and liver endothelial cells: when incubated in UW solution at 4 degrees C for 24 hours and subsequently rewarmed at 37 degrees C, 72% +/- 8% of rat hepatocytes and 81% +/- 5% of liver endothelial cells lost viability. In both cell types, the observed cell damage occurred under an apoptotic morphology; it appeared to be mediated by a rapid increase in the cellular chelatable iron pool by a factor > or =2 (as determined in hepatocytes) and subsequent formation of reactive oxygen species (ROS). Consequently, this cell injury was decreased by iron chelators to 6 to 25% (hepatocytes) and 4% +/- 2% (liver endothelial cells). Deferoxamine nearly completely inhibited the occurrence of apoptotic morphology in both cell types. In liver endothelial cells, cold-induced apoptosis occurring during rewarming after 24 hours of cold incubation in UW solution was far more pronounced than in cell culture medium (loss of viability: 81% +/- 5% vs. 28% +/- 13%), but viability could even be maintained for 2 weeks of cold incubation by use of deferoxamine. In conclusion, this pathological mechanism might be an explanation for the strong endothelial cell injury known to occur after cold preservation. With regard to the extent of this iron-mediated injury, addition of a suitable iron chelator to UW solution might markedly improve the outcome of liver preservation.
Kerkweg
Uta
U
Institut für Physiologische Chemie, Universitätsklinikum, Hufelandstrasse 55, D-45122 Essen, Germany.
Li
Tongju
T
de Groot
Herbert
H
Rauen
Ursula
U
D000241:Adenosine / Q000494:pharmacology*; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003080:Cold Temperature; D005978:Glutathione / Q000494:pharmacology*; D022781:Hepatocytes / Q000473:pathology*; D007328:Insulin / Q000494:pharmacology*; D007501:Iron / Q000502:physiology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D019188:Organ Preservation Solutions; D011887:Raffinose / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism
D007328:Insulin; D007502:Iron Chelating Agents; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D013481:Superoxides; D000493:Allopurinol; D007501:Iron; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose