Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs.
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-kappaB, 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.
Howlett
C E
CE
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa K1H 8M5.
Hutchison
J S
JS
Veinot
J P
JP
Chiu
A
A
Merchant
P
P
Fliss
H
H
D000280:Administration, Inhalation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D004587:Electrophoresis, Agar Gel; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D005980:Glutathione Reductase; D005978:Glutathione