Inhibition of carrageenan-induced paw edema by superoxide dismutase that binds to heparan sulfates on vascular endothelial cells.
The effect of heparin-binding superoxide dismutase (HB-SOD), a fusion gene product consisting of human Cu/Zn-SOD and a C-terminal basic domain with high affinity for heparin-like proteoglycans, was examined on carrageenan-induced paw edema in mice and rats. When injected intravenously to mice just before carrageenan, HB-SOD suppressed significantly paw edema. ED30 of HB-SOD (1000 units/kg) was markedly lower than that of SOD (bovine free Cu/Zn-SOD, 7000 units/kg). When HB-SOD was administered with heparin (500-2000 units/kg), edema was suppressed more markedly than by HB-SOD alone. In contrast, the suppressive action of SOD was decreased by heparin. HB-SOD also suppressed carrageenan paw edema in rats with an ED30 of 2500 units/kg which was also obtained by SOD. Heparin prolonged significantly the duration of HB-SOD suppression of edema. The inhibitory effect of HB-SOD alone disappeared within 5 hr of injection, while more than 80% of the effect remained at this time when HB-SOD has been injected with 1000 units/kg of heparin. Heparin failed to enhance the anti-inflammatory effect of SOD under any of the conditions tested and heparin alone showed no suppression up to 5 hr after injection. HB-SOD might permit studies on pathophysiological events in and around vascular endothelial cells where reactive oxygen species play critical roles.
Oyanagui
Y
Y
Drug Developmental Laboratory, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Sato
S
S
Inoue
M
M
D000818:Animals; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced* / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D011509:Proteoglycans; D011994:Recombinant Proteins; C036090:heparin proteoglycan; D002351:Carrageenan; D006493:Heparin; D013482:Superoxide Dismutase