Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-κB p50
Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-κB p50
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DOI：
10.1152/ajplung.00348.2003
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发表时间：
2004-08-01
影响因子：
4.9
通讯作者：
Laskin, DL
中科院分区：
文献类型：
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作者：
Fakhrzadeh, L;Laskin, JD;Laskin, DL
臭氧诱导的肺损伤与活性氮中间体和TNF-α的产生增加有关，这与致病过程有关。这些介质的产生部分受转录因子的调节，例如。例如，在一个实施例中，NF-κ B和CCAAT/增强子结合蛋白（C/EBP）。目前的研究使用NF-κ B p50基因敲除小鼠来评估这种转录因子蛋白在臭氧诱导的炎症介质产生和毒性中的作用。用臭氧（0.8 ppm，3 h）处理野生型（WT）小鼠导致肺泡巨噬细胞中NF-κ B结合活性迅速增加，在6 - 12 h后达到峰值。这种反应在NF-κ B p50（-/-）小鼠中减弱。在WT小鼠中，而不是NF-κ B p50（-/-）小鼠中，吸入臭氧后巨噬细胞中的C/EBP也显著增加。臭氧还诱导的C/EBP在凝胶迁移试验中的流动性的变化，这表明在控制炎症基因表达可能是重要的转录因子复合物的改变。而来自WT小鼠的巨噬细胞在臭氧吸入后产生增加量的一氧化氮和TNF-α，这在来自NF-κ B p50（-/-）小鼠的细胞中没有观察到。臭氧诱导的抗炎细胞因子IL-10表达的降低也在NF-κ B p50（-/-）小鼠中得到了预防。在野生型小鼠中，臭氧吸入导致支气管肺泡灌洗蛋白（组织损伤的标志物）增加。这在NF-κ B p50（-/-）小鼠中不明显。在这些小鼠中也没有过氧亚硝酸盐介导的肺损伤的证据。这些研究结果表明，NF-κ B和可能的C/EBP信号是重要的臭氧诱导的生产活性氮中间体和TNF-α和组织损伤。
Ozone-induced lung injury is associated with increased production of reactive nitrogen intermediates and TNF-alpha, which have been implicated in the pathogenic process. Generation of these mediators is regulated in part by transcription factors, e. g., NF-kappaB and CCAAT/enhancer-binding protein (C/EBP). The present studies used NF-kappaB p50 knockout mice to assess the role of this transcription factor protein in ozone-induced inflammatory mediator production and toxicity. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in a rapid increase in NF-kappaB binding activity in alveolar macrophages that peaked after 6 - 12 h. This response was attenuated in NF-kappaB p50(-/-) mice. In WT mice, but not NF-kappaB p50(-/-) mice, C/EBP was also markedly increased in macrophages following ozone inhalation. Ozone also induced changes in the mobility of C/EBP in gel shift assays, suggesting alterations in the transcription factor complex that may be important in controlling inflammatory gene expression. Whereas macrophages from WT mice produced increased quantities of nitric oxide and TNF-alpha following ozone inhalation, this was not observed in cells from NF-kappaB p50(-/-) mice. Ozone-induced decreases in expression of the anti-inflammatory cytokine IL-10 were also prevented in NF-kappaB p50(-/-) mice. In WT mice, ozone inhalation caused an increase in bronchoalveolar lavage protein, a marker of tissue damage. This was not evident in NF-kappaB p50(-/-) mice. There was also no evidence of peroxynitrite-mediated lung injury in these mice. These findings demonstrate that NF-kappaB and possibly C/EBP signaling are important in ozone-induced production of reactive nitrogen intermediates and TNF-alpha and in tissue injury.