en
Scientific article
English

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

Published inAmerican journal of respiratory cell and molecular biology, vol. 33, no. 6, p. 555-564
Publication date2005
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
  • Animals
  • Apoptosis
  • Benzamides/pharmacology
  • Blotting, Western
  • Caspase 3
  • Caspases/metabolism
  • Cell Line, Tumor
  • Enzyme Activation
  • Epithelial Cells/enzymology/pathology
  • Fibroblasts/enzymology/pathology
  • Humans
  • Hyperoxia/enzymology
  • In Vitro Techniques
  • L-Lactate Dehydrogenase/metabolism
  • Lung/enzymology/pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly(ADP-ribose) Polymerases/metabolism
  • Pulmonary Alveoli/cytology/metabolism
Citation (ISO format)
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. 555–564. doi: 10.1165/rcmb.2004-0361OC
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Article (Published version)
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Identifiers
ISSN of the journal1044-1549
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