Wong Hector R, Odoms Kelli K, Denenberg Alvin G, Allen Geoffrey L, Shanley Thomas P
Division of Critical Care Medicine, Children's Hospital Medical Center and Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
Shock. 2002 Apr;17(4):274-9. doi: 10.1097/00024382-200204000-00006.
Hyperoxia and tumor necrosis factor-alpha (TNFalpha) are two canonical signals centrally involved in the pathophysiology of acute lung injury. We have attempted to elucidate the effects of these two stimuli on the signal transduction pathways of lung parenchymal cells. In cultured human lung epithelial cells, exposure to hyperoxia alone (95% oxygen) did not affect NF-kappaB activation or degradation of the NF-kappaB inhibitory protein, IkappaB alpha. Stimulation with TNFalpha alone increased NF-kappaB activation within 1 h and induced IkappaB alpha degradation within 0.5 h. After TNFalpha alone, NF-kappaB activation returned to baseline within 2 h and this corresponded with near complete IkappaB alpha resynthesis within 1 h of stimulation. In contrast, simultaneous exposure to hyperoxia and TNFalpha prolonged NF-kappaB activation up to 4 h, and IkappaB alpha degradation up to 2 h after stimulation. Hyperoxia did not affect TNFalpha-mediated resynthesis of IkappaB alpha mRNA. Hyperoxia alone did not induce IkappaB kinase (IKK) activity, but significantly prolonged TNFalpha-mediated activation of IKK activity. Hyperoxia alone did not activate the intercellular adhesion molecule-1 (ICAM-1) promoter, but augmented TNFalpha-mediated activation of the ICAM-1 promoter. These data demonstrate that while hyperoxia alone does not affect activation of NF-kappaB, hyperoxia prolongs TNFalpha-mediated activation of NF-kappaB. The mechanism of this effect involves, in part, prolonged degradation of IkappaB alpha resulting from prolonged activation of IKK.
高氧和肿瘤坏死因子-α（TNFα）是急性肺损伤病理生理学中两个核心的典型信号。我们试图阐明这两种刺激对肺实质细胞信号转导通路的影响。在培养的人肺上皮细胞中，单独暴露于高氧（95%氧气）并不影响NF-κB的激活或NF-κB抑制蛋白IκBα的降解。单独用TNFα刺激可在1小时内增加NF-κB的激活，并在0.5小时内诱导IκBα的降解。单独使用TNFα后，NF-κB的激活在2小时内恢复到基线水平，这与刺激后1小时内IκBα几乎完全重新合成相对应。相比之下，同时暴露于高氧和TNFα可使NF-κB的激活延长至4小时，IκBα的降解在刺激后延长至2小时。高氧不影响TNFα介导的IκBα mRNA的重新合成。单独的高氧不诱导IκB激酶（IKK）活性，但显著延长TNFα介导的IKK活性激活。单独的高氧不激活细胞间黏附分子-1（ICAM-1）启动子，但增强TNFα介导的ICAM-1启动子激活。这些数据表明，虽然单独的高氧不影响NF-κB的激活，但高氧会延长TNFα介导的NF-κB激活。这种效应的机制部分涉及IKK的延长激活导致IκBα的延长降解。
