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题目:: Bleomycin induces alveolar epithelial cell death through JNK-dependent activation of the mitochondrial death pathway.
作者:: Lee(Vivian Y),Schroedl(Clara),Brunelle(Joslyn K),Buccellato(Leonard J),Akinci(Ozkan I),Kaneto(Hideaki),Snyder(Colleen),Eisenbart(James),Budinger(G R Scott),Chandel(Navdeep S)
状态:: 发布时间2005-09-08 , 更新时间 2009-11-19
期刊:: Am J Physiol Lung Cell Mol Physiol
摘要:: Exposure to bleomycin in rodents induces lung injury and fibrosis. Alveolar epithelial cell death has been hypothesized as an initiating mechanism underlying bleomycin-induced lung injury and fibrosis. In the present study we evaluated the contribution of mitochondrial and receptor-meditated death pathways in bleomycin-induced death of mouse alveolar epithelial cells (MLE-12 cells) and primary rat alveolar type II cells. Control MLE-12 cells and primary rat alveolar type II cells died after 48 h of exposure to bleomycin. Both MLE-12 cells and rat alveolar type II cells overexpressing Bcl-X(L) did not undergo cell death in response to bleomycin. Dominant negative Fas-associating protein with a death domain failed to prevent bleomycin-induced cell death in MLE-12 cells. Caspase-8 inhibitor CrmA did not prevent bleomycin-induced cell death in primary rat alveolar type II cells. Furthermore, fibroblast cells deficient in Bax and Bak, but not Bid, were resistant to bleomycin-induced cell death. To determine whether the stress kinase JNK was an upstream regulator of Bax activation, MLE-12 cells were exposed to bleomycin in the presence of an adenovirus encoding a dominant negative JNK. Bleomycin-induced Bax activation was prevented by the expression of a dominant negative JNK in MLE-12 cells. Dominant negative JNK prevented cell death in MLE-12 cells and in primary rat alveolar type II cells exposed to bleomycin. These data indicate that bleomycin induces cell death through a JNK-dependent mitochondrial death pathway in alveolar epithelial cells.
语言:: eng
DOI:: 10.1152/ajplung.00340.2004

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