Prevention of Hepatic Ischemia–Reperfusion Injury by SOD–DIVEMA Conjugate

Abstract

A protective effect of the SOD (superoxide dismutase)–DIVEMA (divinyl ether and maleic anhydride) conjugate on I–R (ischemia–reperfusion) liver injury was demonstrated. Twenty minutes of normothermic hepatic ischemia was induced by clamping the portal triad of Sprague–Dawley rats. Five minutes before the end of ischemia, SOD, SOD–DIVEMA, or NaCl (0.9%) was given intravenously. Using intravital fluorescence microscopy, hepatic microvascular perfusion was analyzed before ischemia and repeatedly during the 120-min reperfusion period. SOD–DIVEMA significantly restored the sinusoidal perfusion rate (control, 98.0 ± 0.5; NaCl, 65.5 ± 7.7; SOD, 81.5 ± 8.2; SOD–DIVEMA, 95.8 ± 0.7%) and reduced the number of leukocytes stagnant in acini (control, 4.4 ± 0.9; NaCl, 36.6 ± 6.3; SOD, 27.7 ± 6.8; SOD–DIVEMA, 12.3 ± 3.3 cells/lobule) and adherent in postsinusoidal venules (control, 55.0 ± 24; NaCl, 417 ± 63; SOD, 253 ± 58; SOD–DIVEMA, 40.0 ± 14 cells/mm2). In addition, SOD–DIVEMA maintained postischemic hepatocellular integrity. The SOD–DIVEMA-treated group revealed higher serum SOD enzyme activity compared to the SOD group after 120 min of reperfusion (SOD–DIVEMA, 33.0 ± 5.9; SOD, 8.6 ± 3.1 U/ml). The beneficial effect of SOD–DIVEMA was most prominent after 120 min of reperfusion, indicating a longer intravascular half-life of SOD–DIVEMA.