Abstract 1921 Poster Session I, Saturday, 5/1 (poster 86)

Inhaled nitric oxide, in combination with high concentrations of oxygen, is administered to newborn infants for the treatment of pulmonary hypertension. Although there have been several controlled trials showing efficacy of inhaled nitric oxide in infants, there has not been a large amount of work looking at the combined oxidative effects of inhaled nitric oxide and oxygen. Therefore, the purpose of this study was to investigate the effects of prolonged exposure of neonatal rats to the combination of inhaled nitric oxide and greater than 95% oxygen. In addition, due to emerging evidence that oxidant-induced gene products may play vital roles in the lung's adaptive and/or protective responses to oxidative stress, we examined the effect of inhaled nitric oxide on the stress response protein, heme oxygenase-1 (HO-1).

Methods: Neonatal Fischer-344 rats were exposed to room air, greater than 95% oxygen, or inhaled nitric oxide 50ppm/greater than 95% oxygen. Twenty-four hours after delivery, the rats were exposed to above conditions for up to seven days. To ensure the health of the mothers and their ability to continue nursing, the mothers were rotated every 24 hours, with a foster mother replacement. The pups were sacrificed after 24, 48, 72, and 96 hours of exposure. Bronchoalveolar lavage fluids and lung tissues were collected. Heme oxygenase protein expression was determined by wen analysis. Statistics were performed using two-way ANOVA.

Results: All animals survived 96 hours of exposure to nitric oxide/oxygen. The animals maintained in room air gained weight faster than did the pups exposed to oxygen or nitric oxide/oxygen. There were no differences in the protein concentrations in the bronchoalveolar lavage fluids in any of the treatment groups. HO-1 protein expressions were not different in any group after 24 hours, but after 48 and 72 hours HO-1 protein levels were greater in the oxygen and nitric oxide/oxygen-exposed animals than in air-breathing controls. After 96 hours, HO-1 levels were higher in the rats exposed to nitric oxide/oxygen than in the rats exposed to oxygen alone.

Conclusions: Upregulation of HO-1 has been demonstrated in neonatal rats exposed to hyperoxia and in cells exposed to nitric oxide donors. The proposed mechanism for the upregulation is thought to be due to damage of cellular membranes by free radicals, allowing access of circulating heme to the cell. The combination of inhaled nitric oxide and oxygen may be acting through similar mechanisms, with upregulation of HO-1 serving as a protective response to oxidative stress in the lung.

Supported in part by Abbott Laboratories