Glutathione protects the rat liver against reperfusion injury after prolonged warm ischemia.
OBJECTIVE
To evaluate the potential of postischemic intravenous infusion of the endogenous antioxidant glutathione (GSH) to protect the liver from reperfusion injury following prolonged warm ischemia.


BACKGROUND
The release of reactive oxygen species (ROS) by activated Kupffer cells (KC) and leukocytes causes reperfusion injury of the liver after warm ischemia. Therefore, safe and cost-effective antioxidant strategies would appear a promising approach to prevent hepatic reperfusion injury during liver resection, but need to be developed.


METHODS
Livers of male Lewis rats were subjected to 60, 90, or 120 minutes of normothermic ischemia. During a 120 minutes reperfusion period either GSH (50, 100 or 200 micromol/h/kg; n= 6-8) or saline (n= 8) was continuously administered via the jugular vein.


RESULTS
Postischemic GSH treatment significantly prevented necrotic injury to hepatocytes as indicated by a 50-60% reduction of serum ALT and AST. After 1 hour of ischemia and 2 hours of reperfusion apoptotic hepatocytes were rare (0.50 +/- 0.10%; mean +/- SD) and not different in GSH-treated animals (0.65 +/- 0.20%). GSH (200 micromol GSH/h/kg) improved survival following 2 hours of ischemia (6 of 9 versus 3 of 9 rats; P < 0.05). Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow. This was paralleled by a reduction of leukocyte adherence to sinusoids and postsinusoidal venules. Intravenous GSH administration resulted in a 10- to 40-fold increase of plasma GSH levels, whereas intracellular GSH contents were unaffected. Plasma concentrations of oxidized glutathione (GSSG) increased up to 5-fold in GSH-treated animals suggesting counteraction of the vascular oxidant stress produced by activated KC.


CONCLUSIONS
Intravenous GSH administration during reperfusion of ischemic livers prevents reperfusion injury in rats. Because GSH is well tolerable also in man, this novel approach could be introduced to human liver surgery.
Schauer
Rolf J
RJ
Department of Surgery, Klinikum of the University of Munich, Grosshadern, Germany. schauer@gch.med.uni-muenchen.de
Gerbes
Alexander L
AL
Vonier
Daniel
D
Meissner
Herbert
H
Michl
Patrick
P
Leiderer
Rosemarie
R
Schildberg
Friedrich W
FW
Messmer
Konrad
K
Bilzer
Manfred
M
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000378:metabolism; D017209:Apoptosis; D002154:Calpain / Q000378:metabolism; D005978:Glutathione / Q000008:administration & dosage* / Q000378:metabolism; D022781:Hepatocytes / Q000648:ultrastructure; D020287:In Situ Nick-End Labeling; D007262:Infusions, Intravenous; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D010084:Oxidation-Reduction; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D000975:Antioxidants; D002154:Calpain; D005978:Glutathione