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Genetic and Pharmacologic Evidence Links Oxidative Stress to Ventilator-induced Lung Injury in Mice

¹ Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health; ² Division of Pulmonary and Critical Care Medicine and ³ Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland; and ⁴ Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan

Correspondence and requests for reprints should be addressed to Sekhar P. Reddy, Ph.D., Department of Environmental Health Sciences/Division of Physiology, Room E7547, 615 North Wolfe Street, Baltimore, MD 21205. E-mail: sreddy{at}jhsph.edu

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.

Key Words: acute lung injury • antioxidant enzymes • mechanical ventilation • Nrf2 • inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The mechanisms by which mechanical ventilation contributes to lung injury are not well understood. What This Study Adds to this Field This study suggests that the pathogenesis of ventilator-associated lung injury involves redox imbalance in the lungs and that the transcription factor Nrf2 has a key protective role by reducing oxidative stress.

 

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