Mechanism of cold ischemia-reperfusion-induced graft injury after orthotopic liver transplantation in rats.
OBJECTIVE
The purpose of this study was to clarify the mechanism of cold ischemia-reperfusion-induced graft injury after liver transplantation, especially with regard to the relationship between hepatocyte, sinusoidal endothelial cell injury, and hepatic hemodynamic alteration.


METHODS
We evaluated changes in hepatocyte and sinusoidal endothelial cell function, and hepatic hemodynamics after reperfusion in an isogeneic rat liver-transplantation model. The livers of male LEW rats were stored in 4 degrees C lactated Ringer's solution for 1 hr, 3 hr (viable graft), and 6 hr (nonviable graft) before implantation. After reperfusion, hepatocyte function was assessed by serum alanine aminotransferase level and bile output; sinusoidal endothelial cell function was evaluated by serum hyaluronic acid level. Furthermore, we measured hepatic venous oxygen saturation, and portal venous blood flow using a transit time blood flow meter.


RESULTS
At 2 hr after reperfusion, the hepatocyte function was similar in all groups. However, the sinusoidal endothelial cell function deteriorated severely in the nonviable graft group, and significantly decreased hepatic venous oxygen saturation levels were observed, suggesting poor hepatic circulation. At 4 hr after reperfusion, the hepatocyte injury was markedly increased in the nonviable graft group. Although systemic blood pressure remained stable, significantly decreased portal venous blood flow in the nonviable graft group was found compared with the viable graft groups. Histopathological studies showed that massive ischemic necrosis was seen in zone III (central) of hepatic lobule 8 hr after reperfusion in the nonviable graft group.


CONCLUSIONS
These data suggest that the sinusoidal endothelial cell injury was predominant in the early phase of reperfusion, and might cause microcirculatory disturbances, resulting in decreased portal venous blood flow. This phenomenon may subsequently cause ischemic damage to the hepatocyte, with eventual graft failure.
Shimizu
H
H
First Department of Surgery, School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan.
Miyazaki
M
M
Ito
H
H
Nakagawa
K
K
Ambiru
S
S
Kato
A
A
Nukui
Y
Y
Nozawa
S
S
Nakajima
N
N
D000818:Animals; D001783:Blood Flow Velocity; D003080:Cold Temperature; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006085:Graft Survival; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology*; D006820:Hyaluronic Acid / Q000097:blood; D008099:Liver / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D008102:Liver Circulation; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D010100:Oxygen / Q000097:blood; D011169:Portal Vein; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D014185:Transplantation, Isogeneic
D006820:Hyaluronic Acid; D010100:Oxygen