OXYGEN-TOXICITY IN MOUSE LUNG - PATHWAYS TO CELL-DEATH

Mice exposed to 100% O-2 die after 3 or 4 d with diffuse alveolar dama ge and alveolar edema. Extensive cell death is evident by electron mic roscopy in the alveolar septa, affecting both endothelial and epitheli al cells. The damaged cells show features of both apoptosis (condensat ion and margination of chromatin) and necrosis (disruption of the plas ma membrane). The electrophoretic pattern of lung DNA indicates both i nternucleosomal fragmentation, characteristic of apoptosis, and overal l degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bar, bcl-x, and Fas, which a re known to be expressed in certain types of apoptosis. However, we di d not detect an increased activity of proteases belonging to the apopt osis ''executioner'' machinery, such as CPP32 (caspase 3), ICE (caspas e 1), or cathepsin D. Furthermore, administration of an ICE-like prote ase inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manif ested 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 .