A 21-aminosteroid reduces hydrogen peroxide generation by and chemiluminescence of stimulated human leukocytes

Leukocytes recruited to regions of focal cerebral ischemia may contribute to tissue injury by their ability to promote inflammation. A novel group of drugs, the 21-aminosteroids, have been observed to reduce neurologic damage and vasogenic cerebral edema in animal models of stroke by inhibiting lipid peroxidation. Production of hydrogen peroxide and free radicals by leukocytes during the inflammatory response may contribute to lipid peroxidation and other consequences of free radical-mediated tissue injury. We assessed the effect of U74500A, a 21-aminosteroid, on the generation of hydrogen peroxide by and on the chemiluminescence of stimulated polymorphonuclear leukocytes and monocytes from normal humans. U74500A significantly reduced the generation of hydrogen peroxide by polymorphonuclear leukocytes (p less than 0.001) and monocytes (p less than 0.01) in a dose-dependent manner. Monocyte chemiluminescence was also significantly inhibited (p less than 0.05), but polymorphonuclear leukocyte-associated chemiluminescence was unchanged. Our results indicate that U74500A can reduce the concentration of oxygen metabolites associated with stimulated human leukocytes, and this effect may explain in part how 21-aminosteroids reduce lipid peroxidation, ischemic injury, and vasogenic edema.