Inhibition of neutrophil leukotriene generation by the 21-aminosteroid, U-74389F.

The 21-aminosteroids are potent inhibitors of iron-dependent lipid peroxidation and more protective than methylprednisolone in models of trauma and reperfusion, but without glucocorticosteroid side effects. Histologically, animals treated with 21-aminosteroids have decreased neutrophil (PMN) infiltrates and diminished tissue destruction associated with trauma or reperfusion. Since PMN contribute to organ failure following ischemia-reperfusion, we assessed the effect of U-74389F (U7), on normal PMN function. Neutrophils from normal volunteers were incubated for 90 min with either vehicle, 15 microM U7 or 80 microM methylprednisolone (MP), in DMSO. Lactoferrin released and generation of leukotrienes to calcium ionophore A23187, also oxygen consumed to PMA and leukotriene B4 (LTB4) and chemotaxis to FMLP and LTB4, were determined for each group of PMN. Lactoferrin released to A23187 was significantly decreased in both steroid groups (7.29 +/- 0.82 micrograms vs 3.06 +/- 0.57 micrograms U7 and 2.88 +/- 0.62 micrograms MP, P < 0.01). PMN incubated with U7 or MP generated significantly less LTB4 (60.6 +/- 4.3 ng vs 47.7 +/- 2.4 ng U7 and 43.3 +/- 5.6 ng MP, P < 0.05). There were no differences noted in the ability of PMN incubated with either compound to consume oxygen or to respond to chemotactic stimuli. We conclude that the proven protective action of the 21-aminosteroids in models of ischemia-reperfusion is related to the ability of "steroids" to inhibit leukotriene generation and degranulation and may be related to the prevention of tissue lipid peroxidation by scavenging oxygen radicals.