Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs

Inhaled nitric oxide (NO), frequently administered in combination with hype roxic gas mixtures, was recently shown to protect against the injurious con sequences of prolonged hyperoxia. We investigated the possibility that this protective effect is attributable to the ability of NO to block pulmonary apoptosis. We show that rats exposed to 100% O-2 for 60 h develop severe lu ng injury consisting of pronounced vascular leak and alveolar apoptosis as inferred from the presence of positive terminal deoxynucleotidyltransferase -mediated dUTP nick, end labeling and DNA ladders in agarose gels and a dec rease in constitutive procaspase-3 levels. However, the inclusion of NO (20 parts/million) in the hyperoxic gas mixture significantly attenuated both the vascular leak and apoptosis. NO reversed the hyperoxia-associated chang es in the activity of the redox-sensitive transcription factors nuclear fac tor-kappa B, activator protein-1, and Sp1 after 24 h, lowered intercellular adhesion molecule-1 levels, and increased glutathione content. We therefor e show, for the first time, that NO can protect against both hyperoxia-indu ced apoptosis and inflammation. The data suggest that this protection may o ccur at the transcriptional and caspase-activation levels.