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1 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa K1H 8M5; 2 Division of Pediatric Intensive Care and 4 Division of Neonatology, Department of Pediatrics, University of Ottawa, Ottawa K1H 8L1; and 3 Department of Laboratory Medicine, Ottawa Hospital, Ottawa, Ontario, Canada K1Y 4E9
Inhaled nitric oxide (NO), frequently
administered in combination with hyperoxic gas mixtures, was recently
shown to protect against the injurious consequences 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% O2
for 60 h develop severe lung 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 decrease 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 changes in the activity of the redox-sensitive transcription factors nuclear factor-
B, activator
protein-1, and Sp1 after 24 h, lowered intercellular
adhesion molecule-1 levels, and increased glutathione content. We
therefore show, for the first time, that NO can protect against both
hyperoxia-induced apoptosis and inflammation. The data suggest that
this protection may occur at the transcriptional and caspase-activation levels.
DNA fragmentation; nuclear factor-B; activator protein-1; Sp1; intercellular adhesion molecule-1; caspase-3
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