EPIDERMAL GROWTH-FACTOR INCREASES ANTIOXIDANT ENZYME AND SURFACTANT SYSTEM-DEVELOPMENT DURING HYPEROXIA AND PROTECTS FETAL-RAT LUNGS IN-VITRO FROM HYPEROXIC TOXICITY

Epidermal growth factor (EGF) has been shown to accelerate fetal lung maturation in rabbits, lambs, and rhesus monkeys in vivo and increase surfactant synthesis in vitro. Its effect on the maturation of the lun g antioxidant enzyme system, however, is unknown. We studied the effec t of EGF (10 nM) on 19-d fetal rat lung explant cultures in serum-free medium in air/5% CO2 or >90% O-2/5 % CO2 compared with similarly grow n control cultures in air or hyperoxia at 72 h. Fetal lung activities of superoxide dismutase and catalase were unchanged by EGF in air, whe reas glutathione peroxidase activity was significantly decreased (p < 0.05 versus air control). However, in hyperoxia, EGF-treated fetal lun g cultures had significantly elevated superoxide dismutase and catalas e activities (p < 0.01) versus O-2-exposed controls, and glutathione p eroxidase activity similar to that of controls. The mRNA levels for al l the antioxidant enzymes showed patterns similar to the enzyme activi ties except in the case of Cu,Zn-superoxide dismutase mRNA, which incr eased in EGF-air cultures. EGF decreased the rate of H-3-choline incor poration into disaturated phosphatidylcholine in air (p < 0.01 versus air control), but increased disaturated phosphatidylcholine synthesis in response to hyperoxia (p < 0.01 versus O-2 control). The histologic appearance of EGF-treated cultures in O-2 was superior to that of O-2 -exposed controls, which showed thickened septal walls, decreased surf actant in the air spaces, and epithelial cell mitochondrial swelling. EGF therefore accelerates antioxidant enzyme and disaturated phosphati dylcholine maturation under hyperoxic conditions and protects fetal ra t lung cultures from hyperoxic injury. This accelerated O-2-dependent maturation by EGF occurs at the pretranslational level. These findings could have clinical implications for premature infants requiring O-2 therapy and at risk for bronchopulmonary dysplasia because of immature pulmonary antioxidant defenses.