Role for nuclear factor-κB in augmented lung injury because of interaction between hyperoxia and high stretch ventilation
Role for nuclear factor-κB in augmented lung injury because of interaction between hyperoxia and high stretch ventilation
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DOI：
10.1016/j.trsl.2009.06.006
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发表时间：
2009-11-01
影响因子：
7.8
通讯作者：
Li, Li-Fu
中科院分区：
文献类型：
--
作者：
Liu, Yung-Yang;Liao, Shuen-Kuei;Li, Li-Fu
急性肺损伤(ALI)患者应用高潮气量机械通气和高氧可引起肺泡凝血和纤维蛋白沉积。高氧血症可增加呼吸机诱导的肺损伤(VILI)，但调节高潮气量机械通气与高氧血症相互作用的机制尚不清楚。我们假设高氧机械牵张通过核因子-kappaB(NF-kappa B)途径协同增加中性粒细胞的渗透和纤溶酶原激活物抑制物-1(PAI-1)的产生。C57BL/6小鼠(每组5只)在给予核因子-kappaB抑制剂(SN-50)2mU g/g后，分别给予高潮气量(30ml/kg)或低潮气量(6ml/kg)机械通气或高氧1~5h。以室内空气或高氧不通风的小鼠为对照组。检测伊文思蓝染色、髓过氧化物酶活性、核蛋白凝胶迁移率变化和炎性细胞因子。免疫组织化学方法检测肿瘤坏死因子-α和纤溶酶原激活物-1的表达。高氧加高潮气量通气量增加的肺损伤，表现为微血管渗漏增加，中性粒细胞向肺内迁移，肿瘤坏死因子-α和活性PAI-1的产生，核因子-kappaB的DNA结合活性和核因子-kappaB的激活。6ml/kg高氧组小鼠中性粒细胞浸润和炎性细胞因子的产生未见统计学意义的增加。SN-50可通过药物抑制核因子-kappaB的活性来减弱高氧诱导的小鼠VILI的增加。我们得出结论，高氧通过激活核因子-kappaB途径增加大潮气量诱导的细胞因子的产生和中性粒细胞的内流。(翻译研究2009；154：228-240)
High-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce alveolar coagulopathy and fibrin depositions within the airways. Hyperoxia has been shown to increase ventilator-induced lung injury (VILI), but the mechanisms that regulate interaction between high-tidal-volume mechanical ventilation and hyperoxia are unclear. We hypothesized that mechanical stretch with hyperoxia synergistically augmented neutrophil infiltration and production of plasminogen activator inhibitor-1 (PAI-1) via the nuclear factor-kappa B (NF-kappa B) pathway. C57BL/6 mice (n = 5 per group) were exposed to high-tidal-volume (30mL/kg) or low-tidal-volume (6mL/kg) mechanical ventilation with room air or hyperoxia for 1 to 5h after 2-mu g/g NF-kappa B inhibitor (SN-50) administration. Nonventilated mice with room air or hyperoxia served as control groups. Evans blue dye, myeloperoxidase, electrophoretic mobility shifting of nuclear protein, and inflammatory cytokine were measured. The expression of tumor necrosis factor-alpha (TNF-alpha) and PAI-1 were studied by immunohistochemistry. The addition of hyperoxia to high-tidal-volume ventilation-augmented lung injury, as demonstrated by increased microvascular leak, neutrophil migration into the lung, TNF-alpha and active PAI-1 production, DNA binding activity of NF-kappa B, and NF-kappa B activation. No statistically significant increase of neutrophil infiltration and inflammatory cytokine production was found in the mice ventilated at 6mL/kg using hyperoxia. Hyperoxia-induced augmentation of VILI was attenuated in mice with pharmacologic inhibition of NF-kappa B activity by SN-50. We conclude that hyperoxia increased high-tidal-volume-induced cytokine production and neutrophil influx through activation of the NF-kappa B pathway. (Translational Research 2009; 154:228-240)