Vol. 298, Issue 3, 894-899, September 2001

Prevention of Neutrophil-Mediated Hepatic Ischemia/Reperfusion Injury by Superoxide Dismutase and Catalase Derivatives

Yoshiyuki Yabe, Naoki Kobayashi, Tsuyoshi Nishihashi, Rei Takahashi, Makiya Nishikawa, Yoshinobu Takakura and Mitsuru Hashida

Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences (Y.Y., N.K., T.N., M.N., Y.T., M.H.), and Department of Pathology and Tumor Biology, Graduate School of Medicine (R.T.), Kyoto University, Sakyo-ku, Kyoto, Japan.

Our previous study demonstrated that the combination of mannosylated superoxide dismutase (Man-SOD) and succinylated catalase (Suc-CAT), both of which are designed to be targeted to liver nonparenchymal cells, is a promising approach to prevent the initial phase of hepatic ischemia/reperfusion injury induced by occlusion of the portal vein for 30 min followed by a 1-h reperfusion in mice. In this study, the preventive effects of these agents were examined on late-phase injury mediated by infiltrating neutrophils, a more severe condition than the initial one. Administration of Suc-CAT alone or with Man-SOD to mice undergoing hepatic ischemia/reperfusion significantly suppressed the expression of intercellular adhesion molecule-1 along the hepatic sinusoid and prevented neutrophil infiltration in the liver. Man-SOD and Suc-CAT also prevented the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase activities after reperfusion lasting 3 and 6 h. Histological evaluation of liver tissues confirmed the efficacy of this treatment, suggesting that these SOD and catalase derivatives have the ability to suppress neutrophil-induced hepatic injury. These results demonstrate that targeted delivery of antioxidant enzymes to liver nonparenchymal cells is a promising approach to reducing the reactive oxygen species produced by Kupffer cells and neutrophils infiltrating into the tissue. Since Suc-CAT is partially taken up by hepatocytes via a catalase-specific uptake mechanism, such a fraction could also be involved in its preventive effect against the injury.