Metal ions and oxygen radical reactions in human inflammatory joint disease

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. H2O2 and O2- are 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 H2O2 in the presence of iron- or copper-ion catalysts. A major determinant of the cytotoxicity of O2- and H2O2 is 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 present in vivo include 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.