Inhaled nitric oxide protects against hyperoxia-induced apoptosis in the rat lung.

Abstract

Inhaled nitric oxide (NO) is frequently administered in combination with hyperoxic gas mixtures to effect pulmonary vasodilation in patients with pulmonary hypertension. NO was recently shown to have a protective effect against the injurious consequences of prolonged hyperoxia. The present study investigated the possibility that this protective effect may be attributable to the ability of NO to block apoptosis. Rats exposed to 100% O2 for 60 h developed severe lung injury consisting of pronounced vascular leak and alveolar apoptosis, as inferred from the presence of DNA fragmentation (positive ISEL staining and DNA ladders in agarose gels), and a decrease in constitutive pro-caspase-3 levels. However, the inclusion of NO (20 ppm) in the hyperoxic gas mixture significantly attenuated both the vascular leak and apoptosis. NO reversed the hyperoxia-associated changes in the activity of the redox-sensitive transcription factors NF-kappaB, AP-1 and Sp1 after 24 h. This protective effect was accompanied by a decrease in the level of the proinflammatory protein ICAM-1 and an increase in the cellular antioxidant glutathione. This study shows for the first time that NO can protect against both hyperoxia-induced apoptosis and vascular leak. The data suggest that the protection may occur at the transcriptional and caspase activation level.