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Published ahead of print on July 3, 2003, doi:10.1165/rcmb.2003-0087RC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 6, December 2003, 779-783

A more recent version of this article appeared on December 1, 2003
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Submitted on March 19, 2003
Revised on June 30, 2003

Inhibition of JNK Pathway Improves Cell Viability in Response to Oxidant Injury

Yuchi Li1*, Yuko Arita1, Hshi-chi Koo1, Jonathan M Davis2, and Jeffrey A Kazzaz2

1 CardioPulmonary Research Institute, Winthrop-University Hospital, Mineola, NY, USA, 2 CardioPulmonary Research Institute, Winthrop-University Hospital, Mineola, NY, USA; School of Medicine, SUNY at Stony Brook, Stony Brook, NY, USA

* To whom correspondence should be addressed. E-mail: liyuchi{at}hotmail.com.

Oxidant insults can lead to apoptotic and non-apoptotic cell death. Lung epithelial cells exposed to high levels of oxygen do not die via apoptosis, but through a much slower, morphologically distinct process involving cell and nuclear swelling. In contrast, H2O2 induces a rapid apoptotic cell death. We first assessed the effect of oxidant exposure on AP-1 (c-Jun and Fos) and c-Jun N-terminal kinase (JNK) regulation in MLE12 cells. Both oxidants induced c-Jun and Fos expression, albeit with a different pattern of regulation-hyperoxia (95% O2) inducing a biphasic response while H2O2 (500 µM) induced a sustained response. We then examined the role of JNK by Western blot, JNK activity assay and a pull down assay and observed an identical pattern of regulation. To assess whether JNK functions in a pro-death or pro-survival capacity, we generated stable cell lines that constitutively express a dominant negative mutation of JNK resulting in significant inhibition of JNK activity. Inhibition of the JNK pathway in this manner prevented hyperoxic and H2O2-induced cell death. These results demonstrate that hyperoxic cell death is pathway driven and that both modes of death involve the JNK signaling pathway.




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