Bleomycin induces alveolar epithelial cell death through JNK-dependent activation of the mitochondrial death pathway
Bleomycin induces alveolar epithelial cell death through JNK-dependent activation of the mitochondrial death pathway
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DOI：
10.1152/ajplung.00340.2004
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发表时间：
2005-10-01
影响因子：
4.9
通讯作者：
Chandel, NS
中科院分区：
文献类型：
--
作者：
Lee, VY;Schroedl, C;Chandel, NS
啮齿类动物暴露于博莱霉素可导致肺损伤和纤维化。肺泡上皮细胞死亡被认为是博莱霉素性肺损伤和纤维化的启动机制。在本研究中，我们评估了线粒体和受体介导的死亡途径在博莱霉素诱导的小鼠肺泡上皮细胞(MLE-12细胞)和原代大鼠肺泡II型细胞死亡中的作用。对照组MLE-12细胞和原代培养的大鼠肺泡II型细胞在染毒48h后死亡。博莱霉素对MLE-12细胞和高表达Bclxl的大鼠肺泡II型细胞均无细胞死亡作用。带有死亡结构域的显性负性Fas结合蛋白不能阻止博莱霉素诱导的MLE-12细胞死亡。Caspase-8抑制剂CrmA不能阻止博莱霉素诱导的原代大鼠肺泡II型细胞死亡。此外，缺乏Bax和Bak的成纤维细胞对博莱霉素诱导的细胞死亡具有抵抗力。为了确定应激激酶JNK是否是Bax激活的上游调节因子，将MLE-12细胞暴露于博莱霉素腺病毒存在下，腺病毒编码显性阴性JNK。在MLE-12细胞中，显性负性JNK的表达可阻止博莱霉素诱导的Bax激活。显性阴性JNK可预防博莱霉素作用下的MLE-12细胞和原代大鼠肺泡II型细胞的死亡。这些数据表明，博莱霉素通过JNK依赖的线粒体死亡途径诱导肺泡上皮细胞死亡。
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-XL 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.