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Oxygen toxicity in mouse lung: pathways to cell death

Horowitz, S
Published in American Journal of Respiratory Cell and Molecular Biology. 1998, vol. 19, no. 4, p. 573-81
Abstract Mice exposed to 100% O2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.
Keywords Amino Acid Chloromethyl Ketones/pharmacologyAnimalsAntigens, CD95/analysis/geneticsApoptosis/drug effects/immunologyBlotting, WesternCaspase 1/metabolismCaspase 3Caspase InhibitorsCaspases/metabolismCathepsin D/metabolismCysteine Proteinase Inhibitors/pharmacologyFas Ligand ProteinGene Expression/immunologyHyperoxia/metabolism/physiopathologyIn Situ Nick-End LabelingLung Diseases/chemically induced/metabolism/physiopathologyMembrane Glycoproteins/analysis/geneticsMiceMice, Inbred C57BLMice, KnockoutNecrosisOxygen/toxicityProto-Oncogene Proteins/geneticsProto-Oncogene Proteins c-bcl-2/geneticsPulmonary Alveoli/chemistry/enzymology/pathologyRNA, Messenger/analysisTumor Suppressor Protein p53/analysis/geneticsBcl-2-Associated X ProteinBcl-X Protein
PMID: 9761753
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Research group Facteurs influençants le développement pulmonaire: étude translationnelle chez l'animal et l'homme (182)
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BARAZZONE, Constance et al. Oxygen toxicity in mouse lung: pathways to cell death. In: American Journal of Respiratory Cell and Molecular Biology, 1998, vol. 19, n° 4, p. 573-81. doi: 10.1165/ajrcmb.19.4.3173 https://archive-ouverte.unige.ch/unige:74626

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