Prevention of hepatic ischemia/reperfusion injury by prolonged delivery of nitric oxide to the circulating blood in mice

Abstract

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.