Tert-butylhydroquinone augments Nrf2-dependent resilience against oxidative stress and improves survival of ventilator-induced lung injury in mice
Veskemaa L, Graw JA, Pickerodt PA, Taher M, Boemke W, Gonzalez-Lopez A, Francis RCE (2021)
Publication Type: Journal article
Publication year: 2021
Journal
American Journal of Physiology-Lung Cellular and Molecular Physiology
American Physiological Society
Book Volume: 320
Pages Range: L17-L28
Journal Issue: 1
DOI: 10.1152/AJPLUNG.00131.2020
Abstract
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 tert-butylhydroquinone (tBHQ) protects against VILI. 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 h. HVT ventilation severely impaired arterial oxygenation (PaO2 = 49 ± 7 mmHg, means ± 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 proinflammatory response, evidenced by lower concentrations of protein and proinflammatory cytokines (IL-1b and TNF-a) 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 proinflammatory response to HVT ventilation in the lung, resulting in 38.5% survival (P = 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.
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Germany (DE)How to cite
APA:
Veskemaa, L., Graw, J.A., Pickerodt, P.A., Taher, M., Boemke, W., Gonzalez-Lopez, A., & Francis, R.C.E. (2021). Tert-butylhydroquinone augments Nrf2-dependent resilience against oxidative stress and improves survival of ventilator-induced lung injury in mice. American Journal of Physiology-Lung Cellular and Molecular Physiology, 320(1), L17-L28. https://doi.org/10.1152/AJPLUNG.00131.2020
MLA:
Veskemaa, Lilly, et al. "Tert-butylhydroquinone augments Nrf2-dependent resilience against oxidative stress and improves survival of ventilator-induced lung injury in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 320.1 (2021): L17-L28.
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