Tert-butylhydroquinone augments Nrf2-dependent resilience against oxidative stress and improves survival of ventilator-induced lung injury in mice.

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 (HVT) ventilation for a maximum of 4 hours. RESULTS HVT 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 HVT ventilation. In addition, tBHQ attenuated the HVT 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 HVT 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 HVT 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.