Prevention of hepatic ischemia/reperfusion injury by prolonged delivery of nitric oxide to the circulating blood in mice.
BACKGROUND
To protect hepatocytes from ischemia/reperfusion injury in mice, prolonged delivery of nitric oxide (NO) to the liver was performed by a bolus intravenous injection of polyethylene glycol (PEG)-conjugated bovine serum albumin (BSA) with about 10 NO molecules attached via an S-nitrosothiol linkage (PEG-poly SNO-BSA).


METHODS
A hepatic ischemia/reperfusion injury was induced in mice by occluding the portal vein and the hepatic artery for 15 min followed by 6 hours of reperfusion. Each NO donor was injected into the tail vein just before the initiation of the reperfusion at a dose of 2 micromol NO/kg.


RESULTS
The ischemia followed by reperfusion resulted in a striking increase in plasma alanine aminotransferase and aspartate aminotransferase activities. S-nitroso-N-acetyl penicillamine and NO-BSA, two classical S-nitrosothiols, had no statistically significant effect in preventing elevation of the markers. In marked contrast, PEG-poly SNO-BSA significantly (P<0.01) suppressed it. In addition, PEG-poly SNO-BSA significantly (P<0.01) reduced the number of neutrophils infiltrating into the liver and prevented the excessive production of NO from inducible NO synthase in the liver.


CONCLUSIONS
These results indicate that PEG-poly SNO-BSA can be used to prevent hepatic ischemia/reperfusion injury.
Katsumi
Hidemasa
H
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Nishikawa
Makiya
M
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D006499:Hepatic Artery; D008099:Liver / Q000293:injuries*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000097:blood / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011169:Portal Vein; D015427:Reperfusion Injury / Q000517:prevention & control*
D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase