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1 Lung Cellular and Molecular Biology Laboratory, Hadassah-Hebrew University Medical Center, Institute of Pulmonology, Jerusalem, Israel
2 Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
3 Lung Cellular and Molecular Biology Laboratory, Hadassah-Hebrew University Medical Center, Institute of Pulmonology, Jerusalem, Israel; Pulmonary Center, Boston University School of Medicine, Boston, MA, USA; Department of Pathology, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: dayanmd{at}012.net.il.
Epithelial cells are considered to be a main target of bleomycin-induced lung injury, which leads to fibrosis in vivo. We studied the characteristics of in vitro bleomycin-induced apoptosis in a mouse lung epithelial (MLE) cell line. Bleomycin caused an increase of reactive oxygen species (ROS) resulting in oxidative stress, mitochondrial leakage and apoptosis. These were associated with elevated caspase-8 and resultant caspase-9 activity and with up-regulation of Fas expression. Glutathione and inhibitors of caspase-8 or caspase-9, but not of FasL, inhibited these effects, suggesting their dependence on ROS, caspase-8 and -9, in a Fas/FasL independent pathway. However, post-bleomycin-exposed MLE cells were more sensitive to Fas-mediated apoptosis. These results demonstrate that the initial bleomycin-induced oxidative stress causes a direct apoptotic effect in lung epithelial cells involving a regulatory role of caspase-8 on caspase-9. Fas represents an amplification mechanism, and not a direct trigger of bleomycin-induced epithelial cell apoptosis.
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