ATTENUATION OF ACUTE LUNG INJURY AND OXYGEN RADICAL PRODUCTION BY THE21-AMINOSTEROID, U-78518F

Oxygen radicals play an important role in the mechanism of acute lung injury. The 21-aminosteroid lazaroid, U-78518F, is a potent antioxidan t. We examined the effect of intravenous U-78518F on acute lung injury in septic guinea pigs over 8 h. The experimental groups (n = 6) were 1) saline control, 2) Escherichia coli (2 x 10(9)/kg iv), 3) pretreatm ent (U-78518F 5 mg/kg bolus + 1 mg . kg-1 . h-1, 15 min before E. coli injection), and 4) posttreatment (U-78518F 30 min after E. coli injec tion). We measured wet-to-dry weight ratio (W/D) as an index of pulmon ary edema and concentration ratios of I-125-labeled albumin in lung ti ssue and bronchoalveolar lavage fluid compared with plasma (L/P and BA L/P, respectively) as indexes of lung protein fluxes. In septic guinea pigs, pretreatment with U-78518F attenuated W/D, L/P, and BAL/P and p osttreatment attenuated W/D and BAL/P (P < 0.05 for each). Furthermore , we studied the effect of U-78518F on human neutrophil oxygen radical production (ORP) by using flow cytometry to assess intracellular ORP and lucigenin-dependent chemiluminescence to assess extracellular ORP. Neutrophils (5 X 10(5)) were stimulated with 0.5 mug/ml of phorbol my ristate acetate. With flow cytometry, we measured intracellular ORP, c ross-sectional cell area, and degranulation in neutrophils. U-78518F ( minimum concn 1.0 muM) decreased intracellular ORP (n = 4; P < 0.05) w hen the dihydrorhodamine 123 assay was used. U-78518F (minimum concn 1 .0 muM) inhibited phorbol myristate acetate-induced neutrophil chemilu minescence (n = 4; P < 0.05). In conclusion, this study demonstrates t hat U-78518F attenuates acute lung injury and decreases neutrophil int racellular and extracellular ORP.