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Poly(ADP-ribose)polymerase activation mediates lung epithelial cell death in vitro but is not essential in hyperoxia-induced lung injury

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Published in American Journal of Respiratory Cell and Molecular Biology. 2005, vol. 33, no. 6, p. 555-64
Abstract Hyperoxia induces extensive DNA damage and lung cell death by apoptotic and nonapoptotic pathways. We analyzed the regulation of Poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme activated by DNA damage, and its relation to cell death during hyperoxia in vitro and in vivo. In lung epithelial-derived A549 cells, which are known to die by necrosis when exposed to oxygen, a minimal amount of PARP-1 was cleaved, correlating with the absence of active caspase-3. Conversely, in primary lung fibroblasts, which die mainly by apoptosis, the complete cleavage of PARP-1 was concomitant to the induction of active caspase-3, as assessed by Western blot and caspase activity. Blockade of caspase activity by Z-VAD reduced the amount of cleaved PARP-1 in fibroblasts. Hyperoxia induced PARP activity in both cell types, as revealed by poly-ADP-ribose accumulation. In A549 cells, the final outcome of necrosis was dependent on PARP activity because it was prevented by the PARP inhibitor 3-aminobenzamide. In contrast, apoptosis of lung fibroblasts was not sensitive to 3-aminobenzamide and was not affected by PARP-1 deletion. In vivo, despite evidence of PARP activation in hyperoxia-exposed mouse lungs, absence of PARP-1 did not change the extent of lung damage, arguing for redundant oxidative stress-induced cell death pathways.
Keywords AnimalsApoptosisBenzamides/pharmacologyBlotting, WesternCaspase 3Caspases/metabolismCell Line, TumorEnzyme ActivationEpithelial Cells/enzymology/pathologyFibroblasts/enzymology/pathologyHumansHyperoxia/enzymologyIn Vitro TechniquesL-Lactate Dehydrogenase/metabolismLung/enzymology/pathologyMiceMice, Inbred C57BLMice, KnockoutPoly(ADP-ribose) Polymerases/metabolismPulmonary Alveoli/cytology/metabolism
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PMID: 16151053
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Article (Published version) (408 Kb) - document accessible for UNIGE members only Limited access to UNIGE
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Research group Facteurs influençants le développement pulmonaire: étude translationnelle chez l'animal et l'homme (182)
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PAGANO AURRAND-LIONS, Alessandra et al. Poly(ADP-ribose)polymerase activation mediates lung epithelial cell death in vitro but is not essential in hyperoxia-induced lung injury. In: American Journal of Respiratory Cell and Molecular Biology, 2005, vol. 33, n° 6, p. 555-64. https://archive-ouverte.unige.ch/unige:46633

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Deposited on : 2015-02-12

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