Abstract
The role of extracellular superoxide in the pathogenesis of vasogenic edema was studied using transgenic mice expressing a 5-fold increase in extracellular superoxide dismutase (EC-SOD) activity in their brains. Increased EC-SOD expression offered significant protection against edema development after cold-induced injury (44% less edema than nontransgenic littermates, p < 0.05). Since iron may contribute to vasogenic edema by catalyzing the production of hydroxyl radical from superoxide and hydrogen peroxide, the effects of the chelator deferoxamine were studied. Deferoxamine reduced edema formation after cold-induced injury (43% less edema than controls, p < 0.05); however, treatment with iron-saturated deferoxamine also reduced edema development in mice (32-48% less edema, p < 0.05). This suggested that the protection offered by deferoxamine was independent of its ability to chelate iron. An iron-independent mechanism by which superoxide can contribute to vasogenic edema is via reaction with nitric oxide to produce the potentially toxic peroxynitrite anion, which is also scavenged by deferoxamine. Mice treated with an inhibitor of nitric oxide synthase were protected against cold-induced edema (37% less edema, p < 0.05). EC-SOD transgenic mice received no additional protection by inhibition of nitric oxide synthesis, supporting this novel alternative mechanism of edema formation.
Highlights
The role of extracellular superoxide in the pathogenesis of vasogenic edema was studied using transgenic mice expressing a 5-fold increase in extracellular superoxide dismutase (EC-SOD) activity in their brains
An iron-independent mechanism by which superoxide can contribute to vasogenic edema is via reaction with nitric oxide to produce the potentially toxic peroxynitrite anion, which is scavenged by deferoxamine
EC-SOD transgenic mice expressed a 5-fold increase in EC-SOD activity in the brain compared to nontransgenic littermates as previously deexpress messenger RNA for the human EC-SODgene as well as increased levels of EC-SOD activity in brain, heart, and skeletal muscle
Summary
(Received for publication, January 8, 1993, and in revised form, March 22, 1993). From the Departmentsof $Pathology and llMedicine, Duke University Medical Center, Durham, North Carolina 27710. An iron-independent mechanism by which superoxide can contribute to vasogenic edema is via reaction with nitric oxide to produce the potentially toxic peroxynitrite anion, which is scavenged by deferoxamine. The production of hydroxyl radicals from superoxide in a reaction that is independent of catalytic transition metals has been proposed and supported experimentally [11, 12] In this reaction superoxide (0;)reacts with nitric oxide (NO') ( k = 3.7 X lo M".s" [13]) to form the potentially toxic peroxynitrite anion (ONOO-, Reaction 3) [14]. Peroxynitrite has a pK, of 6.5 [15, 16] and once protonated, forms peroxynitrous acid which rapidly decomposes by homolytic cleavage to produce hydroxyl radical ('OH) and nitrogen dioxide (NOn,Reaction 4) These reactions may contribute to the pathogenesis of vasogenic edema but have not yet been examined experimentally. Analysis of variance with a Fisher PLSD test was used to compare significance in group 6. p values less than 0.05 were considered to be significant
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