Liu Yung-Yang, Liao Shuen-Kuei, Huang Chung-Chi, Tsai Ying-Huang, Quinn Deborah A, Li Li-Fu
Chest Department, Taipei Veterans General Hospital, and National Yang-Ming University, School of Medicine, Taipei, Taiwan.
Transl Res. 2009 Nov;154(5):228-40. doi: 10.1016/j.trsl.2009.06.006. Epub 2009 Jul 14.
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-kappaB (NF-kappaB) pathway. C57BL/6 mice (n=5 per group) were exposed to high-tidal-volume (30 mL/kg) or low-tidal-volume (6 mL/kg) mechanical ventilation with room air or hyperoxia for 1 to 5h after 2-microg/g NF-kappaB 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-kappaB, and NF-kappaB activation. No statistically significant increase of neutrophil infiltration and inflammatory cytokine production was found in the mice ventilated at 6 mL/kg using hyperoxia. Hyperoxia-induced augmentation of VILI was attenuated in mice with pharmacologic inhibition of NF-kappaB activity by SN-50. We conclude that hyperoxia increased high-tidal-volume-induced cytokine production and neutrophil influx through activation of the NF-kappaB pathway.
急性肺损伤（ALI）患者使用高潮气量机械通气和高氧可诱发肺泡凝血病和气道内纤维蛋白沉积。高氧已被证明会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之间相互作用的机制尚不清楚。我们推测，高氧状态下的机械牵张通过核因子-κB（NF-κB）途径协同增强中性粒细胞浸润和纤溶酶原激活物抑制剂-1（PAI-1）的产生。给予2μg/g NF-κB抑制剂（SN-50）后，将C57BL/6小鼠（每组n = 5）暴露于室空气或高氧环境下进行高潮气量（30 mL/kg）或低潮气量（6 mL/kg）机械通气1至5小时。以室空气或高氧环境下未通气的小鼠作为对照组。检测伊文思蓝染料、髓过氧化物酶、核蛋白的电泳迁移率以及炎性细胞因子。通过免疫组织化学研究肿瘤坏死因子-α（TNF-α）和PAI-1的表达。与高潮气量通气相比，高氧环境下通气会加重肺损伤，表现为微血管渗漏增加、中性粒细胞向肺内迁移、TNF-α和活性PAI-1产生增加、NF-κB的DNA结合活性以及NF-κB激活。在使用高氧以6 mL/kg进行通气的小鼠中，未发现中性粒细胞浸润和炎性细胞因子产生有统计学意义的增加。通过SN-50对NF-κB活性进行药理抑制后，高氧诱导的VILI加重情况在小鼠中有所减轻。我们得出结论，高氧通过激活NF-κB途径增加了高潮气量诱导的细胞因子产生和中性粒细胞流入。
