Inhibitory effects of safe and novel SOD derivatives, galactosylated-SOD, on hepatic warm ischemia/reperfusion injury in pigs.
OBJECTIVE
Oxygen-derived free radicals such as superoxide play an important role in ischemia/reperfusion (IR) injury during and after extensive liver surgery or liver transplantation. Superoxide dismutase (SOD) has protective effects against hepatic IR injury. The effect of native SOD is, however, limited because of rapid elimination from the blood circulation and poor affinity for liver cells. It was reported by our collaborators that a SOD derivative modified with galactose (Gal-SOD) was selectively delivered well to hepatocytes by direct attachment to galactose receptors. In the present study, the efficacy of this agent for attenuating hepatic warm IR injury was investigated using the pig model.


METHODS
After 45-min clamping of the hepatic artery and portal vein, pigs were divided into 3 groups according to the following treatments. Ten milliliters of normal saline in Group 1 (n=5), 10,000 units/kg of native SOD in Group 2 (n=5) and 10,000 units/kg of Gal-SOD in Group 3 (n=5) were given just prior to hepatic reperfusion. Liver function including clearance of total bile acid (TBA) and hyaluronic acid (HA) was investigated. Lipid peroxidase of the liver tissue (LPO) and histological findings were examined. In addition, survival rates of the pigs in each group were evaluated.


RESULTS
The survival rates at the 7th day after the operation were 60%, 80%, 100% in Groups 1, 2 and 3, respectively. Liver function tests, clearance of TBA and HA, and LPO levels were significantly improved in Groups 3 over findings in Groups 1 and 2. Congestion of hepatic tissues and vacuolization of hepatocytes in Group 3 were less than those in Groups 1 and 2. These results suggested that oxygen-derived free radicals were scavenged by Gal-SOD and IR injury was attenuated.


CONCLUSIONS
A safe and novel agent, Gal-SOD has a protective effect against hepatic warm IR injury.
Yuzawa
H
H
Department of Surgery II, Nagasaki University School of Medicine Nagasaki, Japan.
Fujioka
H
H
Mizoe
A
A
Azuma
T
T
Furui
J
J
Nishikawa
M
M
Hashida
M
M
Kanematsu
T
T
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000097:blood; D005260:Female; D005690:Galactose / Q000494:pharmacology*; D006820:Hyaluronic Acid / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008111:Liver Function Tests; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000494:pharmacology*; D016019:Survival Analysis; D013552:Swine; D016896:Treatment Outcome
D000975:Antioxidants; D001647:Bile Acids and Salts; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D013482:Superoxide Dismutase; D005690:Galactose