MAPK pathways mediate hyperoxia-induced oncotic cell death in lung epithelial cells
MAPK pathways mediate hyperoxia-induced oncotic cell death in lung epithelial cells
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DOI：
10.1016/s0891-5849(03)00494-5
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发表时间：
2003-10-15
影响因子：
7.4
通讯作者：
Mantell, LL
中科院分区：
文献类型：
--
作者：
Romashko, J;Horowitz, S;Mantell, LL
肺上皮细胞损伤和细胞死亡在长时间高氧动物急性肺损伤的发病机制中起重要作用。本研究旨在揭示高氧诱导肺上皮细胞死亡的分子机制。细胞死亡被认为要么是细胞凋亡，表型缩小，半胱天冬酶被激活，要么是肿瘤，细胞器肿胀。暴露于95% O-2（高氧）诱导MLE-12细胞死亡，伴有细胞和细胞核肿胀、细胞质空泡形成、线粒体结构和酶功能丧失。没有检测到caspase-3活性升高和磷脂酰丝氨酸易位，这表明在高氧条件下，MLE-12细胞通过肿瘤而不是凋亡而死亡。此外，高氧触发了转录因子AP-1以及丝裂原活化蛋白激酶（MAPK）家族成员p38和JNK的持续激活。重要的是，当AP-1、p38或JNK激活被特异性抑制剂或显性阴性DNA构建体抑制时，MLE-12细胞在高氧条件下的存活率显著增强，这表明在肺上皮细胞中，高氧诱导了程序驱动的肿瘤，涉及AP-1、JNK和p38 MAPK。有趣的是，过氧化氢诱导MLE-12细胞的氧化性凋亡，核形态缩小，caspase-3活性活化，也由AP-1、JNK和p38介导。因此，我们的数据表明，尽管氧化性肿瘤和细胞凋亡具有不同的下游事件，但它们具有共同的上游JNK/p38和AP-1通路，可以作为减少高氧炎性肺损伤的潜在靶点。(C) 2003 Elsevier Inc.
Cell injury and cell death of pulmonary epithelium plays an important role in the pathogenesis of acute lung injury in animals exposed to prolonged hyperoxia. The aim of this study was to decipher the molecular mechanisms modulating cell death induced by hyperoxia in lung epithelium. Cell death is thought to be either apoptotic, with shrinking phenotypes and activated caspases, or oncotic, with swelling organelles. Exposure to 95% O-2 (hyperoxia) induced cell death of MLE-12 cells with cellular as well as nuclear swelling, cytosolic vacuolation, and loss of mitochondrial structure and enzyme function. Neither elevated caspase-3 activity nor phosphatidylserine translocation were detected, suggesting that in hyperoxia, MLE-12 cells die via oncosis rather than apoptosis. In addition, hyperoxia triggered a sustained activation of the transcription factor AP-1, as well as mitogen-activated protein kinase (MAPK) family members p38 and JNK. Importantly, survival of MLE-12 cells in hyperoxia was significantly enhanced when either AP-1, p38, or JNK activation was inhibited by either specific inhibitors or dominant negative DNA constructs, indicating that in lung epithelial cells hyperoxia induces a program-driven oncosis, involving AP-1, JNK, and p38 MAPK. Interestingly, hydrogen peroxide-induced oxidative apoptosis of MLE-12 cells, with a shrinking nuclear morphology and activated caspase-3 activity, is also mediated by AP-1, JNK, and p38. Therefore, our data indicate that although they have divergent downstream events, oxidative oncosis and apoptosis share upstream JNK/p38 and AP-1 pathways, which could be used as potential targets for reducing hyperoxic inflammatory lung injury. (C) 2003 Elsevier Inc.