Protection against acute and chronic hyperoxic inhibition of neonatal rat lung development with the 21-aminosteroid drug U74389F

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 μm, internal surface area = 1014 cm²; O₂ controls = 61.0 μm (↑29%), 769 cm² (↓24%); O₂ 21-AS = 53.4 μm (↑13%), 919 cm² (↓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. The right ventricle hypertrophy (2° to pulmonary hypertension) in the O₂ controls reaching adulthood [right ventricle/left ventricle + septum weight = 0.496 (↑55% versus air control value = 0.320)] was markedly reduced in the adult 21-AS animals exposed to hyperoxia as neonates [0.382 (↑19%)]. Thus, 21-AS treatment had a substantial protective effect against both the acute and chronic lung as well as cardiac morphologic changes that early life exposure to hyperoxia can produce.