Published ahead of print on September 27, 2007, doi:10.1164/rccm.200701-060OC Am. J. Respir. Crit. Care Med., Volume 176, Number 12, December 2007, 1222-1235 A more recent version of this article appeared on December 15, 2007
Submitted on January 11, 2007 Genetic and Pharmacologic Evidence Links Oxidative Stressto Ventilator-Induced Lung Injury in MiceSrinivas Papaiahgari1,1 Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 2 Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA, 3 Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA, 4 Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan * To whom correspondence should be addressed. 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 which regulates the induction of several antioxidant enzymes, enhances susceptibility to ventilator-induced lung injury (VILI), while antioxidant supplementation attenuates such effect. Methods: To test our hypothesis and to examine the relevance of oxidative stress in VILI, here we have assessed lung injury and inflammatory responses in Nrf2-deficient (Nrf2-/-) mice and wildtype (Nrf2+/+) animals following 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 to Nrf2+/+ mice. Nrf2-deficieny enhances the levels of several pro-inflammatory 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 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: Collectively, 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, gene expression
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