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

• Published in: American journal of respiratory and critical care medicine 2007-12, Vol.176 (12), p.1222-1235
• Main Authors: Papaiahgari, Srinivas, Yerrapureddy, Adi, Reddy, Swetha R, Reddy, Narsa M, Dodd-O, Jeffery M, Crow, Michael T, Grigoryev, Dimitry N, Barnes, Kathleen, Tuder, Rubin M, Yamamoto, Masayuki, Kensler, Thomas W, Biswal, Shyam, Mitzner, Wayne, Hassoun, Paul M, Reddy, Sekhar P
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Adult and adolescent clinical studies; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antioxidants; Antioxidants - metabolism; Anxiety disorders. Neuroses; Biological and medical sciences; C. Critical Care; Capillary Permeability - drug effects; Capillary Permeability - physiology; Cytokines; Cytokines - immunology; Disease Models, Animal; Emergency and intensive respiratory care; Enzymes; Free Radical Scavengers - pharmacology; Genes; Hypotheses; Inflammation; Inflammation - prevention & control; Intensive care medicine; Lungs; Male; Medical sciences; Mice; Mice, Knockout; Mortality; NF-E2-Related Factor 2 - genetics; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - immunology; Pathogenesis; Permeability; Post-traumatic stress disorder; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Respiratory distress syndrome; Respiratory Distress Syndrome, Adult - drug therapy; Respiratory Distress Syndrome, Adult - immunology; Respiratory Distress Syndrome, Adult - physiopathology; Transcription factors; Ventilation; Ventilators; Ventilators, Mechanical - adverse effects
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200701-060OC

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. 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. 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. 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. 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.