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

Am J Physiol Lung Cell Mol Physiol. 2021 Jan 1;320(1):L17-L28. doi: 10.1152/ajplung.00131.2020. Epub 2020 Oct 7.

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 ([Formula: see text] = 49 ± 7 mmHg, means ± SD) and respiratory system compliance, resulting in a 100% mortality among controls. Compared with controls, tBHQ improved arterial oxygenation ([Formula: see text] = 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-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 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.

Keywords: VILI; lung; redox; tBHQ; ventilation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidant Response Elements
  • Antioxidants / pharmacology
  • Bronchoalveolar Lavage Fluid
  • Cytokines / metabolism
  • Gene Expression Regulation*
  • Hydroquinones / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress*
  • Protective Agents / pharmacology*
  • Pulmonary Edema / etiology
  • Pulmonary Edema / prevention & control*
  • Respiration, Artificial / adverse effects
  • Survival Rate
  • Ventilator-Induced Lung Injury / drug therapy
  • Ventilator-Induced Lung Injury / etiology
  • Ventilator-Induced Lung Injury / mortality*
  • Ventilator-Induced Lung Injury / pathology

Substances

  • Antioxidants
  • Cytokines
  • Hydroquinones
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Protective Agents
  • 2-tert-butylhydroquinone