Attenuation of acute lung injury and oxygen radical production by the 21-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 antioxidant. 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 i.v.), 3) pretreatment (U-78518F 5 mg/kg bolus + 1 mg.kg-1 x h-1, 15 min before E. coli injection), and 4) posttreatment (U-78518F 30 min after E. coli injection). We measured wet-to-dry weight ratio (W/D) as an index of pulmonary edema and concentration ratios of 125I-labeled albumin in lung tissue and bronchoalveolar lavage fluid compared with plasma (L/P and BAL/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 posttreatment 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 micrograms/ml of phorbol myristate acetate. With flow cytometry, we measured intracellular ORP, cross-sectional cell area, and degranulation in neutrophils. U-78518F (minimum concn 1.0 microM) decreased intracellular ORP (n = 4; P < 0.05) when the dihydrorhodamine 123 assay was used. U-78518F (minimum concn 1.0 microM) inhibited phorbol myristate acetate-induced neutrophil chemiluminescence (n = 4; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Tanigaki
T
T
Department of Medicine, Stanford University Medical Center, California 94305.
Suzuki
Y
Y
Heimer
D
D
Sussman
H H
HH
Ross
W G
WG
Raffin
T A
TA
D000166:Acridines; D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002860:Chromium Radioisotopes; D004927:Escherichia coli Infections / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D005021:Ethylamines / Q000627:therapeutic use*; D005434:Flow Cytometry; D006168:Guinea Pigs; D007958:Leukocyte Count; D008163:Luminescent Measurements; D008171:Lung Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012711:Serum Albumin, Radio-Iodinated; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000166:Acridines; D000975:Antioxidants; D002860:Chromium Radioisotopes; D005021:Ethylamines; D010879:Piperazines; D011725:Pyridines; D017382:Reactive Oxygen Species; D012711:Serum Albumin, Radio-Iodinated; C072017:U 78518F; C033472:10,10'-dimethyl-9,9'-biacridinium; D013755:Tetradecanoylphorbol Acetate