Received for publication December 27, 2005.
Revised February 16, 2006.
Accepted for publication February 17, 2006.

ATTENUATION OF OXYGEN-INDUCED ABNORMAL LUNG MATURATION IN RATS BY RETINOIC ACID: POSSIBLE ROLE OF CYTOCHROME P4501A ENZYMES

Abstract

Supplemental oxygen is frequently used in the treatment of infants having pulmonary insufficiency, but prolonged hyperoxia may contribute to the development of bronchopulmonary dysplasia (BPD) in these infants. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury. Retinoic acid (RA) plays a key role in lung development. Here, we tested the hypotheses that newborn rats exposed to a combination of RA and hyperoxia would be less susceptible to lung injury than those exposed to hyperoxia only, and that modulation of CYP1A enzymes by RA contribute to the beneficial effects of RA against hyperoxic lung injury. Newborn rats exposed to hyperoxia for 7 days showed higher lung weight/body weight (LW/BW) ratios compared to those exposed to RA + hyperoxia. Hyperoxia for 7 days also caused a significant increase in hepatic and pulmonary CYP1A1/1A2 expression compared to air-breathing controls. RA + hyperoxia treatment lowered the expression of these genes. Seven to 30 days after withdrawal of hyperoxia, the animals showed marked induction of hepatic and pulmonary CYP1A1/1A2 expression, but animals that had been given RA + hyperoxia displayed lower expression of these enzymes. On postnatal days (PND) 22 or 38, the hyperoxic animals displayed retarded lung alveolarization; however, the RA + hyperoxia-exposed animals showed improved alveolarization. The improved alveolarization in animals given RA + hyperoxia, in conjunction with the attenuation of CYP1A1 and 1A2 expression in these animals suggests that this phenomenon may play a role in the beneficial effects of RA.

Key words: abnormal lung maturation, cytochrome P4501A, hyperoxia, lung, newborn rat, retinoic acid