Visit our Expo - Redox and Inflammation signaling 2012

Session XV : Reactive oxygen species and cell signaling Poster XV, 1
Evidence for a defective lung NF-kB activation by oxidative stress in cystic fibrosis cell
culture and mouse models
Emilie Boncoeur, Olivier Tabary, Elise Bonvin, Annick Clément, Alexandra Henrion-
Caude, Jacky Jacquot.
Inserm U 719, Hôpital Saint-Antoine, UPMC ParisVI, 75571, Paris, France
Lung in patients with cystic fibrosis (CF) is characterized by structural damage and altered
repair due to oxidative stress. To gain insights into the oxidative stress-related damage in CF
lung, we studied the effects of hyperoxia (95 % O2) in CF and normal mouse lung and cell
culture models. In normal lung epithelium, protection against hyperoxic injury has been
shown to be related to an increased expression of the cell cycle inhibitor p21WAF1/CIP1 thus
confering a survival advantage to damaged cells and to increased NF-kB activity by involving
a cytoplasm-to-nucleus translocation after degradation of the inhibitor protein IkB alpha by
the proteasome machinery. Here we demonstrate in CF in vivo and in vitro models that
hyperoxia did not induce neither increased p21WAF1/CIP1 expression nor lung NF-kB
activation IkB alpha degradation, nor induction of caspase 3 and subsequent apoptosis but,
unexpectedly caused enhanced proteasome activity, in contrast to that observed in normal in
vivo and in vitro controls. Interestingly, ectopic expression of p21WAF1/CIP1 in hyperoxiaexposed
CF lung epithelial cells or treatment with the selective proteasome inhibitor MG132
restored the NF-kB activation and IkB alpha degradation which was associated with an
increased caspase-3 activity and apoptotic cell death. Our data suggest that the use of
proteasome inhibitors or related substances modulating p21WAF1/CIP1 degradation,
promoting the activation of NF-kB in hyperoxic conditions could be a valuable approach to
protect lung epithelial cells from oxidative stress in CF patients.
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