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Vol. 295, Issue 3, 904-911, December 2000

Protective Effect of S-Nitrosylated alpha 1-Protease Inhibitor on Hepatic Ischemia-Reperfusion Injury1

Norisato Ikebe , Takaaki Akaike, Yoichi Miyamoto, Kazuyuki Hayashida , Jun Yoshitake, Michio Ogawa and Hiroshi Maeda

Department of Microbiology (N.I., T.A., Y.M., K.H., J.Y., H.M.) and 2nd Department of Surgery (N.I., K.H., M.O.), Kumamoto University School of Medicine, Kumamoto, Japan

S-Nitrosylated compounds (nitrosothiols; RS-NOs) function as nitric oxide (NO) reservoirs and preserve the antioxidant activities of NO. We found remarkable cytoprotection by an S-nitrosylated protease inhibitor from human plasma, S-nitroso-alpha 1-protease inhibitor (S-NO-alpha 1-PI) that possesses a completely nitrosylated SH group, in hepatic ischemia-reperfusion injuries in rats. Liver ischemia was induced in rats by occluding both the portal vein and hepatic artery for 30 min and was followed by reperfusion. S-NO-alpha 1-PI and control compounds such as native alpha 1-PI, an NO synthase (NOS) inhibitor, and standard RS-NOs were given via the portal vein just after reperfusion was initiated. Liver injury was evaluated by measuring the extracellular release of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). Infiltration of neutrophils and induction of apoptosis and heme oxygenase-1 (HO-1) in the liver were also examined. Maximal liver injury occurred at 3 h after reperfusion and then decreased gradually. Not only did S-NO-alpha 1-PI treatment (0.1 µmol; 5.3 mg/rat) greatly reduce elevation of liver enzymes in plasma, as well as neutrophil accumulation and apoptotic change in liver, it also improved the impaired hepatic blood flow as assessed by laser Doppler flowmetry and potentiated the induction of HO-1 in the liver. Although native alpha 1-PI moderately reduced liver injury, low molecular weight RS-NOs such as S-nitrosoglutathione and S-nitroso-N-acetyl penicillamine produced no obvious protective effect. An NOS inhibitor exacerbated the hepatic ischemia-reperfusion injuries. These results suggest that S-NO-alpha 1-PI exerts a potent cytoprotective effect on ischemia-reperfusion liver injury by maintaining tissue blood flow, inducing HO-1, and suppressing neutrophil-induced liver damage and apoptosis.

1 This work was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (to Y.M. and T.A.), and grants from the Ministry of Health and Welfare of Japan (to T.A.).

0022-3565/00/2953-0904$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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