Department of Anesthesiology and Operative Intensive Care Medicine CCM/CVK, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
CIBER-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Am J Physiol Lung Cell Mol Physiol. 2021 Jan 1;320(1):L17-L28. doi: 10.1152/ajplung.00131.2020. Epub 2020 Oct 7.
Oxidative stress caused by mechanical ventilation contributes to the pathophysiology of ventilator-induced lung injury (VILI). A key mechanism maintaining redox balance is the upregulation of nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant gene expression. We tested whether pretreatment with an Nrf2-antioxidant response element (ARE) pathway activator -butylhydroquinone (tBHQ) protects against VILI. Male C57BL/6J mice were pretreated with an intraperitoneal injection of tBHQ ( = 10), an equivalent volume of 3% ethanol (EtOH3%, vehicle, = 13), or phosphate-buffered saline (controls, = 10) and were then subjected to high tidal volume (HV) ventilation for a maximum of 4 h. HV ventilation severely impaired arterial oxygenation ( = 49 ± 7 mmHg, means ± SD) and respiratory system compliance, resulting in a 100% mortality among controls. Compared with controls, tBHQ improved arterial oxygenation ( = 90 ± 41 mmHg) and respiratory system compliance after HV ventilation. In addition, tBHQ attenuated the HV ventilation-induced development of lung edema and proinflammatory response, evidenced by lower concentrations of protein and proinflammatory cytokines (IL-1β and TNF-α) in the bronchoalveolar lavage fluid, respectively. Moreover, tBHQ enhanced the pulmonary redox capacity, indicated by enhanced Nrf2-depentent gene expression at baseline and by the highest total glutathione concentration after HV ventilation among all groups. Overall, tBHQ pretreatment resulted in 60% survival ( < 0.001 vs. controls). Interestingly, compared with controls, EtOH3% reduced the proinflammatory response to HV ventilation in the lung, resulting in 38.5% survival ( = 0.0054 vs. controls). In this murine model of VILI, tBHQ increases the pulmonary redox capacity by activating the Nrf2-ARE pathway and protects against VILI. These findings support the efficacy of pharmacological Nrf2-ARE pathway activation to increase resilience against oxidative stress during injurious mechanical ventilation.
机械通气引起的氧化应激导致呼吸机诱导的肺损伤 (VILI) 的病理生理学变化。维持氧化还原平衡的一个关键机制是核因子-红细胞 2 相关因子 2 (Nrf2) 依赖性抗氧化基因表达的上调。我们测试了 Nrf2-抗氧化反应元件 (ARE) 途径激活剂丁羟氢醌 (tBHQ) 预处理是否可以预防 VILI。雄性 C57BL/6J 小鼠接受腹腔注射 tBHQ(=10)、等体积 3%乙醇 (EtOH3%，载体，=13) 或磷酸盐缓冲盐水 (对照，=10) 预处理，然后接受高潮气量 (HV) 通气，最长 4 小时。HV 通气严重损害动脉氧合 (=49 ± 7 mmHg，平均值 ± 标准差) 和呼吸系统顺应性，导致对照组 100%死亡。与对照组相比，tBHQ 改善了 HV 通气后的动脉氧合 (=90 ± 41 mmHg) 和呼吸系统顺应性。此外，tBHQ 减轻了 HV 通气引起的肺水肿和促炎反应的发展，这表现在支气管肺泡灌洗液中蛋白质和促炎细胞因子 (IL-1β 和 TNF-α) 的浓度分别降低。此外，tBHQ 增强了肺的氧化还原能力，表现在 HV 通气后所有组中基线时 Nrf2 依赖性基因表达增强和总谷胱甘肽浓度最高。总的来说，tBHQ 预处理的存活率为 60%(<0.001 与对照组相比)。有趣的是，与对照组相比，EtOH3% 降低了肺对 HV 通气的促炎反应，存活率为 38.5%(=0.0054 与对照组相比)。在这种 VILI 的小鼠模型中，tBHQ 通过激活 Nrf2-ARE 途径增加肺的氧化还原能力并预防 VILI。这些发现支持使用药理学 Nrf2-ARE 途径激活来增加在有创性机械通气期间对抗氧化应激的弹性。
