Attenuation of Oxygen-Induced Abnormal Lung Maturation in Rats by Retinoic Acid: Possible Role of Cytochrome P4501A Enzymes
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas (X.I.C., Y.W.L., W.J., B.M.); and Department of Pathology, Methodist Hospital, Houston, Texas (R.B.)
- Address correspondence to:
Dr. Xanthi I. Couroucli, Assistant Professor of Pediatrics, Baylor College of Medicine, 6621 Fannin, F.C. 530.01, Houston, TX 77030. E-mail: xanthic{at}bcm.tmc.edu
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 in these infants. Cytochrome P4501A 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 ratios compared with those exposed to RA + hyperoxia. Hyperoxia for 7 days also caused a significant increase in hepatic and pulmonary CYP1A1/1A2 expression compared with 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 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.
Footnotes
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This work was supported in part by National Heart, Lung, and Blood Institute Grant KO8 HL04333 to X.I.C., and Grants RO1 ES009132 and RO1 HL070921 from the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute, respectively, to B.M.
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doi:10.1124/jpet.105.100677.
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ABBREVIATIONS: BPD, bronchopulmonary dysplasia; ROS, reactive oxygen species; P450, cytochrome P450; Ah, aryl hydrocarbon; AHR, Ah receptor; RA, retinoic acid; RAR; retinoic acid receptor; RXR, retinoic acid X receptor; CO, corn oil; PND, postnatal day(s); LW/BW, liver weight/body weight; EROD, ethoxyresourufin O-deethylase; MROD, methoxyresorufin O-demethylase; AHRE, Ah response element; RT-PCR, reverse transcriptase-polymerase chain reaction; CYC, cyclophilin; ANOVA, analysis of variance; PAH, polycyclic aromatic hydrocarbon; VEGF, vascular endothelial growth factor.
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- Received December 26, 2005.
- Accepted February 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
