Metal ions and oxygen radical reactions in human inflammatory joint disease

Abstract

Activated phagocytic cells produce superoxide (O₂^-) and hydrogen peroxide (H₂O₂) ; their production is important in bacterial killing by neutrophils and has been implicated in tissue damage by activated phagocytes. H₂O₂and O₂are poorly reactive in aqueous solution and their damaging actions may be related to formation of more reactive species from them. One such species is hydroxyl radical (OH^.), formed from H₂O₂in the presence of iron- or copper-ion catalysts. A major determinant of the cytotoxicity of O^-₂and H₂O₂is thus the availability and location of metal-ion catalysts of OH* formation. Hydroxyl radical is an initiator of lipid peroxidation. Iron promoters of OH* production presentin vivoinclude ferritin, and loosely bound iron complexes detectable by the ‘bleomycin assay’. The chelating agent Desferal (desferrioxamine B methanesulphonate) prevents iron-dependent formation of OH* and protects against phagocyte-dependent tissue injury in several animal models of human disease. The use of Desferal for human treatment should be approached with caution, because preliminary results upon human rheumatoid patients have revealed side effects. It is proposed that OH* radical is a major damaging agent in the inflamed rheumatoid joint and that its formation is facilitated by the release of iron from transferrin, which can be achieved at the low pH present in the micro-environment created by adherent activated phagocytic cells. It is further proposed that one function of lactoferrin is to protect against iron-dependent radical reactions rather than to act as a catalyst of OH· production.