Prevention of neutrophil-mediated hepatic ischemia/reperfusion injury by superoxide dismutase and catalase derivatives.
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.
Yabe
Y
Y
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Kobayashi
N
N
Nishihashi
T
T
Takahashi
R
R
Nishikawa
M
M
Takakura
Y
Y
Hashida
M
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002374:Catalase / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000473:pathology / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000627:therapeutic use*
D018799:Intercellular Adhesion Molecule-1; D002374:Catalase; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase