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Updated: Jul 11, 2026
A Mouse Model of Orotracheal Intubation and Ventilated Lung Ischemia Reperfusion Surgery
Published on: September 9, 2022
Genetic and pharmacologic evidence links oxidative stress to ventilator-induced lung injury in mice
Srinivas Papaiahgari1, Adi Yerrapureddy, Swetha R Reddy
1Department of Environmental Health Sciences/Division of Physiology, Room E7547, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Rationale:
Mechanical ventilation (MV) is an indispensable therapy for critically ill patients with acute lung injury and the adult respiratory distress syndrome. However, the mechanisms by which conventional MV induces lung injury remain unclear.
Objectives:
We hypothesized that disruption of the gene encoding Nrf2, a transcription factor that regulates the induction of several antioxidant enzymes, enhances susceptibility to ventilator-induced lung injury (VILI) and that antioxidant supplementation attenuates this effect.
Methods:
To test our hypothesis and to examine the relevance of oxidative stress in VILI, we assessed lung injury and inflammatory responses in Nrf2-deficient (Nrf2(-/-)) mice and wild-type (Nrf2(+/+)) mice after an acute (2-h) injurious model of MV with or without administration of antioxidant.
Measurements And Main Results:
Nrf2(-/-) mice displayed greater levels of lung alveolar and vascular permeability and inflammatory responses to MV as compared with Nrf2(+/+) mice. Nrf2 deficiency enhances the levels of several proinflammatory cytokines implicated in the pathogenesis of VILI. We found diminished levels of critical antioxidant enzymes and redox imbalance by MV in the lungs of Nrf2(-/-) mice; however, antioxidant supplementation to Nrf2(-/-) mice remarkably attenuated VILI. When subjected to a clinically relevant prolong period of MV, Nrf2(-/-) mice displayed greater levels of VILI than Nrf2(+/+) mice. Expression profiling revealed lack of induction of several VILI genes, stress response and solute carrier proteins, and phosphatases in Nrf2(-/-) mice.
Conclusions:
Our data demonstrate for the first time a critical role for Nrf2 in VILI, which confers protection against cellular responses induced by MV by modulating oxidative stress.
Insights
Mice lacking the Nrf2 gene showed increased susceptibility to ventilator-induced lung injury (VILI). Antioxidant treatment protected against VILI, highlighting Nrf2
Area of Science:
- Critical care medicine
- Pulmonary medicine
- Molecular biology
Background:
- Mechanical ventilation (MV) is crucial for acute lung injury and ARDS patients.
- Mechanisms of MV-induced lung injury are not fully understood.
- Oxidative stress is implicated in ventilator-induced lung injury (VILI).
Purpose of the Study:
- Investigate the role of Nrf2 in VILI.
- Determine if Nrf2 deficiency increases susceptibility to VILI.
- Assess the protective effect of antioxidant supplementation against VILI.
Main Methods:
- Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice were used.
- An acute (2-h) injurious MV model was employed.
- Lung injury, inflammation, and gene expression were assessed with and without antioxidant treatment.
Main Results:
- Nrf2(-/-) mice exhibited increased lung permeability and inflammation compared to Nrf2(+/+) mice.
- MV led to diminished antioxidant enzymes and redox imbalance in Nrf2(-/-) mice.
- Antioxidant supplementation significantly attenuated VILI in Nrf2(-/-) mice, and prolonged MV worsened VILI in these mice.
Conclusions:
- Nrf2 plays a critical protective role in mitigating ventilator-induced lung injury.
- Nrf2 modulates oxidative stress responses to mechanical ventilation.
- Targeting Nrf2 pathways may offer therapeutic strategies for VILI.
