Normal lung development involves septation of the large air saccules present at birth to form smaller diameter alveoli with a much increased surface area for respiratory exchange. This process in the newborn animal is markedly inhibited by hyperoxia, and the altered lung morphology that results may be permanent. We tested whether treatment of neonatal rats with the new 21-aminosteroid (21-AS) drug, U-74389F (15 mg/kg/d), could protect against O2-induced inhibition of normal lung development. By morphometric analysis after 10 d in > 95% O2, the lungs of the animals treated with this potent iron chelator and inhibitor of lipid peroxidation showed a substantial protective effect--with reduced mean air space diameter and significantly increased internal surface area compared with O2 control pups. [Air control mean air space diameter = 47.4 microns, internal surface area = 1014 cm2; O2 controls = 61.0 microns (increases 29%), 769 cm2 (decreases 24%); O2 21-AS = 53.4 microns (increases 13%), 919 cm2 (decreases 9%); p < 0.05 between O2 groups.] Similarly, inhibition of lung elastin deposition (involved in septation process) during hyperoxia was significantly ameliorated by 21-AS treatment. In addition, follow-up studies of young adult rats demonstrated permanently enlarged lung alveoli and reduced surface area after neonatal high O2 exposure. These chronic morphologic effects were also significantly reduced by neonatal 21-AS treatment.(ABSTRACT TRUNCATED AT 250 WORDS)