Oxygen toxicity to the developing lung of the mouse: role of reactive oxygen species.
Since the description of bronchopulmonary dysplasia (BPD) in premature infants, the supplemental oxygen administered has been suspect in the etiology of BPD. This has prompted studies on the effect of hyperoxia on lung growth in neonatal animals. So far, these have not led to a treatment which either prevents or mitigates BPD. Another approach to investigate the effect of hyperoxia on the immature lung is to use lung explants from 12-d gestation mouse fetuses. Exposing explants to different concentrations of oxygen for 48 h, we found that exposures to oxygen both below (10%) and above (35% or greater) normoxia adversely affected branching morphogenesis and growth. The effect was irreversible at exposures of 50% oxygen and greater. To determine the role of reactive oxygen species (ROS) in the effect of hyperoxia, antioxidants and inhibitors of ROS formation were added to the incubating explants, and their influence on reducing the adverse effect of 50% oxygen was assessed. The combination of CuZn superoxide dismutase (SOD) and catalase, manganese SOD, manganese-3-tetrakis(1-methyl-4-pyridyl)porphorin, a low molecular weight SOD mimetic, and to a lesser extent, deferoximine, an antioxidant and inhibitor of hydroxyl radical formation, were successful in reducing the effect of 50% oxygen on morphogenesis. Not successful were N-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase); allopurinol (an inhibitor of xanthine oxidase); N-acetylcysteine and ebselen (a glutathione peroxidase mimetic); Trolox (a synthetic tocopherol); catalase, and CuZnSOD used alone. These results provide evidence that superoxide anion and possibly hydroxyl radical are the ROS most likely responsible for the growth effects of hyperoxia on mouse fetal lung morphogenesis.
Wilborn
A M
AM
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Evers
L B
LB
Canada
A T
AT
D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018496:Hyperoxia / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000196:embryology; D051379:Mice; D008815:Mice, Inbred Strains; D009024:Morphogenesis; D010100:Oxygen / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000502:physiology*
D017382:Reactive Oxygen Species; D010100:Oxygen