Background: Oxidative stress caused by mechanical ventilation contributes to the pathophysiology of ventilator-induced lung injury (VILI). A key mechanism maintaining redox balance is the up-regulation of Nrf2-dependent antioxidant gene expression. We tested whether pretreatment with a Nrf2-ARE pathway activator tert-butylhydroquinone (tBHQ) protects against VILI. Methods: Male C57BL/6J mice were pretreated with an intraperitoneal injection of tBHQ (n=10), an equivalent volume of 3% ethanol (EtOH3%, vehicle, n=13), or phosphate buffered saline (controls, n=10), and were then subjected to high tidal volume (HV_T) ventilation for a maximum of 4 hours. Results: HV_T ventilation severely impaired arterial oxygenation (PaO₂ = 49±7 mmHg, mean±SD) and respiratory system compliance, resulting in a 100% mortality among controls. Compared with controls, tBHQ improved arterial oxygenation (PaO₂ = 90±41 mmHg) and respiratory system compliance after HV_T ventilation. In addition, tBHQ attenuated the HV_T ventilation induced development of lung edema and pro-inflammatory response, evidenced by lower concentrations of protein and pro-inflammatory cytokines (IL-1β, 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_T ventilation among all groups. Overall, tBHQ pretreatment resulted in 60% survival (p<0.001 vs. controls). Interestingly, compared with controls, EtOH3% reduced the pro-inflammatory response to HV_T ventilation in the lung resulting in 38.5% survival (p=0.0054 vs. controls). Conclusions: 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

中文翻译：

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叔丁基氢醌增强了Nrf2依赖的抗氧化应激能力，并改善了呼吸机诱发的小鼠肺损伤的存活率

背景：机械通气引起的氧化应激有助于呼吸机诱发的肺损伤（VILI）的病理生理。维持氧化还原平衡的关键机制是Nrf2依赖性抗氧化剂基因表达的上调。我们测试了用Nrf2-ARE途径活化剂叔丁基对苯二酚（tBHQ）进行预处理是否可以预防VILI。方法：雄性C57BL / 6J小鼠经腹膜内注射tBHQ（n = 10），等体积的3％乙醇（EtOH3％，赋形剂，n = 13）或磷酸盐缓冲液（对照组，n = 10）进行预处理，然后进行高潮气量（HV _T）通风，最多持续4个小时。结果：HV _T通气严重损害了动脉氧合（PaO ₂= 49±7 mmHg，平均值±SD）和呼吸系统顺应性，导致对照组中100％的死亡率。与对照组相比，tBHQ改善了HV _T通气后的动脉氧合（PaO ₂ = 90±41 mmHg）和呼吸系统顺应性。此外，tBHQ减弱了HV _T通气诱导的肺水肿和促炎反应的发展，这分别由支气管肺泡灌洗液中较低的蛋白质和促炎细胞因子（IL-1β，TNF-α）浓度来证明。此外，tBHQ增强了肺的氧化还原能力，表现为基线时Nrf2依赖的基因表达增强，HV _T后总谷胱甘肽浓度最高所有组之间进行通风。总体而言，tBHQ预处理可导致60％的存活率（与对照组相比，p <0.001）。有趣的是，与对照组相比，EtOH3％降低了肺对HV _T通气的促炎反应，从而导致38.5％的存活率（与对照组相比，p = 0.0054）。结论：在这种VILI鼠模型中，tBHQ通过激活Nrf2-ARE途径增加肺氧化还原能力并防御VILI。这些发现支持了药理学的功效