Superoxide anion radical as an indirect mediator in ocular inflammatory disease

Intravitreal injection of a superoxide-generating reaction mixture of xanthine oxidase and xanthine, either with or without rabbit plasma, was shown to be a mediator of an intense uveal and retinal inflammation in pigmented and albino rabbits. Controls of heat-inactivated xanthine oxidase with or without rabbit plasma, or plasma by itself, was without effect on ocular tissues. Xanthine alone as a control exhibited little or no inflammatory response. Controls of active xanthine oxidase by itself, or with rabbit plasma, produced a very strong inflammatory response that may represent enzymic reaction with endogenous xanthine. When the superoxide generating reaction mixture was given intravitreally the reaction began in the anterior segment within 16 hours and reached its peak after 2 days. The response in the posterior segment was delayed and did not become evident until after at least 24 hours, and may be due to the close proximity of the anterior chamber to the ciliary processes where cellular exudates first appear. Anterior segment uveitis began to recede after 4 days but posterior segment inflammation persisted beyond 6 days, and in many instances, led to retinitis, and retinal detachment. Superoxide dismutase was effectively used in vitro to quench superoxide in the reaction mixture but it did not prevent inflammatory reactions in vivo because it was found to possess strong toxic qualities of its own in ocular tissues. Other free radicals of oxygen, as well as hydrogen peroxide, can develop with the breakdown of superoxide, and cause tissue damage. A known ability of superoxide to convert a plasma precursor into a factor chemotactic for neutrophils may also cause superoxide production in situ by accumulating neutrophils. Because phagocytes are potential sources of superoxide, this study provides a good experimental model for studying the influence of oxygen free radicals in ocular inflammatory disease.