Modulation of Pulmonary Cytochrome P4501A1 Expression by Hyperoxia and Inhaled Nitric Oxide in the Newborn Rat: Implications for Lung Injury

Abstract

Inhaled nitric oxide (iNO), with supplemental oxygen, is used in the treatment of hypoxic respiratory failure of the newborn.In this study, we tested the hypothesis that exposure of newborn rats to iNO, hyperoxia, or iNO ϩ hyperoxia would modulate the expression of pulmonary cytochrome P450 (CYP)1A1 in relation to acute lung injury. Newborn Fischer 344 rats were maintained in room air, or exposed to iNO, hyperoxia (Ͼ95%), or iNO (20 or 40 ppm) ϩ hyperoxia for up to 168 h, and lung injury parameters and CYP1A1 expression were studied. Animals given iNO (40 ppm) ϩ hyperoxia were more susceptible to lung injury than those exposed to hyperoxia or iNO alone. On the other hand, animals exposed to iNO (20 ppm) ϩ hyperoxia did not elicit lung damage. Pulmonary CYP1A1 protein and mRNA expression were induced by hyperoxia, iNO (20 or 40 ppm), or iNO (20 ppm) ϩ hyperoxia for up to 168 h, compared with air-breathing controls. In animals given iNO (40 ppm) ϩ hyperoxia, pulmonary CYP1A1 was enhanced at 48 h, followed by downregulation at later time points. Immunohistochemistry experiments showed localization of CYP1A1 in the pulmonary epithelial and endothelial cells. In conclusion, because previous studies have shown beneficial effects of CYP1A1 induction in hyperoxic lung injury, our current observations showing maintenance of pulmonary CYP1A1 induction by iNO (20 ppm) ϩ hyperoxia through the 168-h period support the hypothesis that this phenomenon may contribute to the protective effects of iNO against hyperoxic injury. (Pediatr Res 59: [401][402][403][404][405][406] 2006)

Attenuation of Oxygen-Induced Abnormal Lung Maturation in Rats by Retinoic Acid: Possible Role of Cytochrome P4501A Enzymes

“…1) and the histological evidence of lung damage (Fig. 2) was in agreement with previous studies showing acute lung injury in newborn rats exposed to prolonged hyperoxia (Bucher and Roberts, 1981;Couroucli et al, 2006). The protection of lung injury by RA (Figs.…”

Hyperoxia-induced changes in estradiol metabolism in postnatal airway smooth muscle

“…First, we demonstrate that estrogen metabolism via CYP1a1 can occur in the lung. Previous work has shown CYP1a1 expression in airway epithelial, airway alveolar, and airway endothelial cells (7) and its presence in vascular smooth muscle cells (11). No other studies to date have discussed metabolism in the neonatal lung or more specifically fASM.…”

NO Inhibits Hyperoxia-Induced NF-κB Activation in Neonatal Pulmonary Microvascular Endothelial Cells

“…Pulmonary endothelial cells of newborn mice exposed to hyperoxia demonstrate structural alterations including polymorphonuclear leukocyte and platelet adhesion (21). Fewer inflammatory cells were seen in newborn rats exposed to NO plus hyperoxia when compared to oxygen exposed controls (22). Thus, it appears that NO acts in part by limiting inflammatory cell recruitment in the newborn lung, thus limiting the extent of hyperoxic lung injury.…”