Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway
Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway
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DOI：
10.1152/ajplung.00300.2004
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发表时间：
2006-04-01
影响因子：
4.9
通讯作者：
Breuer, R
中科院分区：
文献类型：
--
作者：
Wallach-Dayan, SB;Izbicki, G;Breuer, R
上皮细胞被认为是博莱霉素性肺损伤的主要靶点，在体内可导致纤维化。我们研究了博莱霉素体外诱导小鼠肺上皮细胞系(MLE)凋亡的特征。博莱霉素引起体内活性氧簇(ROS)的增加，导致氧化应激、线粒体泄漏和细胞凋亡。这与caspase-8和由此产生的caspase-9活性以及Fas表达上调有关。谷胱甘肽和caspase-8或caspase-9的抑制剂，但不能抑制FasL的作用，提示它们依赖于ROS，caspase-8和-9，这是一条Fas/FasL非依赖的途径。然而，博莱霉素作用后的MLE细胞对Fas介导的细胞凋亡更为敏感。这些结果表明，最初博莱霉素诱导的氧化应激导致肺上皮细胞的直接凋亡效应，涉及caspase-8对caspase-9的调节作用。Fas是一种放大机制，而不是博莱霉素诱导的上皮细胞凋亡的直接触发因素。
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 upregulation 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, postbleomycin-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.