Hyperoxia inhibits oxidant-induced apoptosis in lung epithelial cells
Hyperoxia inhibits oxidant-induced apoptosis in lung epithelial cells
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DOI：
10.1074/jbc.m004716200
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发表时间：
2001-01-05
影响因子：
4.8
通讯作者：
Mantell, LL
中科院分区：
文献类型：
--
作者：
Franek, WR;Horowitz, S;Mantell, LL
以往的研究表明，高氧可诱导培养的肺上皮细胞非凋亡性死亡，而过氧化氢(H_2O_2)和百草枯可引起细胞凋亡，以检测导致肺上皮细胞氧化凋亡的途径是否对分子O-2敏感。与室内空气对照相比，预先暴露在高氧环境中的细胞中，过氧化氢诱导的细胞凋亡程度显著降低。将耐高氧的HeLa-80细胞预先暴露于80%O-2也可抑制氧化剂诱导的细胞凋亡，提示这种抑制作用不是由于O-2毒性所致。由于高氧产生活性氧物种并激活氧化还原敏感的转录因子核因子kappaB(NF-kappaB)，因此我们研究了抗氧化酶和核因子-kappaB在这一抑制过程中的作用。抑制作用的开始似乎与I kappaB的降解和随后的NF-kappaB的激活(无论是由高氧还是由肿瘤坏死因子-α)直接相关，但没有发现内源性抗氧化酶活性的显著上调。此外，通过将I kappaB的显性-负性突变结构导入A549细胞，抑制核因子-kappaB的活性显著增加了H_2O_2诱导的细胞凋亡的程度。这些数据表明，高氧抑制氧化剂诱导的细胞凋亡，这种抑制是由核因子-kappaB介导的。
It has previously been shown that hyperoxia induces non-apoptotic cell death in cultured lung epithelial cells, whereas hydrogen peroxide (H2O2) and paraquat cause apoptosis, To test whether pathways leading to oxidative apoptosis in epithelial cells are sensitive to molecular O-2, A549 cells were exposed to 95% O-2, prior to exposure to lethal concentrations of H2O2. The extent of H2O2-induced apoptosis was significantly reduced in cells preexposed to hyperoxia compared with room-air controls. Preexposure of the hyperoxia-resistant HeLa-80 cell line to 80% O-2 also inhibited oxidant-induced apoptosis, suggesting that this inhibition is not due to O-2, toxicity. Because hyperoxia generates reactive oxygen species and activates the redox-sensitive transcription factor nuclear factor kappaB (NF-kappaB), the role of antioxidant enzymes and NF-kappaB were examined in this inhibitory process. The onset of inhibition appeared to be directly related to the degradation of I kappaB and subsequent activation of NF-kappaB (either by hyperoxia or TNF-alpha), whereas no significant up-regulation of endogenous antioxidant enzyme activities was found. In addition, suppression of NF-kappaB activities by transfecting A549 cells with a dominant-negative mutant construct of I kappaB significantly augmented the extent of H2O2-induced apoptosis. These data suggest that hyperoxia inhibits oxidant-induced apoptosis and that this inhibition is mediated by NF-kappaB.