| Research Abstract |
Though active oxygen species have been postulated to play important roles in the pathogenesis of various diseases, critical evidence supporting this hypothesis is lacking. Since these hazardous species rapidly react with bioactive molecules, they should be scavenged at the site of generation. To localize superoxide dismutase (SOD) at the site of tissue injury, we have developed three types of SOD derivatives, SM-SOD,AC-SOD,AH-SOD,MAN-SOD,GAL-SOD, and HB-SOD. SM-SOD circulates bound to albumin with prolonged in vivo half-life and accumulates in tissues whose pH is decreased. AC-SOD is an acylated SOD that binds to membrane/lipid bilayers of cornea and other tissues. AH-SOD is a cationic SOD that selectively accumulates in the proximal tubules of the kidney. MAN-SOD and GAL-SOD are hepatophilic SOD derivatives linked with mannose and galactose residues and specifically localized in sinusoidal cells and hepatocytes, respectively. HB-SOD is a fusion gene product having a structure of human Cu/Zn-SOD and C-terminal heparin-binding domain.
When injected intravenously, SM-SOD markedly inhibited posticschemic reperfusion injury of the brain, heart, liver and other tissues. Through binding to the corneal surface, AC-SOD significantly decreased endotoxin-induced corneal injury particularly at is early stage of inflammation. The infiltration of neutrophils to the avascular cornea was also inhibited by AC-SOD. HB-SOD binds to vascular endothelial cells and undergoes transendothelial movement where it efficiently dismutates superoxide radicals. Using these SOD derivatives, the roles of superoxide radicals in the pathogenesis of various types of tissue injury were tested. HB-SOD also inhibited vasogenic tissue injury, such as brain edema, and exhibited depressor action in spontaneously hypertensive rat, an animal model of essential hypertension. These results indicate that superoxide radicals play critical roles in the pathogenesis of these diseases.
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