The effects of several free radical scavengers and antioxidant enzymes on neutrophil-mediated changes in mucosal permeability (measured using blood-to-lumen clearance of 51Cr-labeled ethylene-diaminetetraactate) were assessed using ileal loops perfused with N-formyl-methionyl-leucyl-phenylalanine (FMLP). Neither superoxide dismutase nor catalase reduced the FMLP-induced increase in mucosal permeability. However, manganese-loaded desferrioxamine (a superoxide dismutase mimetic), PZ51 (a glutathione peroxidase analogue), desferrioxamine (an iron chelator), or dimethylsulfoxide (a hydroxyl radical scavenger) significantly attenuated FMLP-induced mucosal damage. The results of our experiments indicate that neutrophilic oxidants are responsible for a major portion of the mucosal permeability changes induced by FMLP.