Genetic and pharmacologic evidence links oxidative stress to ventilator-induced lung injury in mice.

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.

[1]  W. MacNee,et al.  Oxidants/antioxidants and chronic obstructive pulmonary disease: pathogenesis to therapy. , 2008, Novartis Foundation symposium.

[2]  H. Yoshioka,et al.  Association Between Heat Stress Protein 70 Induction and Decreased Pulmonary Fibrosis in an Animal Model of Acute Lung Injury , 2007, Lung.

[3]  S. Reddy,et al.  Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  S. Reddy,et al.  EGFR-activated signaling and actin remodeling regulate cyclic stretch-induced NRF2-ARE activation. , 2007, American journal of respiratory cell and molecular biology.

[5]  E. Kiss-Toth,et al.  Tribbles: a family of kinase-like proteins with potent signalling regulatory function. , 2007, Cellular signalling.

[6]  M. Sporn,et al.  Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. , 2006, Biochemical and biophysical research communications.

[7]  S. Reddy,et al.  Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[8]  Wei-Zen Sun,et al.  Oxidative stress during 1-lung ventilation. , 2006, The Journal of thoracic and cardiovascular surgery.

[9]  R. Strieter,et al.  The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury. , 2006, Seminars in respiratory and critical care medicine.

[10]  L. Ware.  Pathophysiology of acute lung injury and the acute respiratory distress syndrome. , 2006, Seminars in respiratory and critical care medicine.

[11]  Simon C Watkins,et al.  Gene expression profiling of target genes in ventilator-induced lung injury. , 2006, Physiological genomics.

[12]  Masayuki Yamamoto,et al.  Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. , 2006, The Journal of clinical investigation.

[13]  R. Glenny,et al.  Computational identification of key biological modules and transcription factors in acute lung injury. , 2006, American journal of respiratory and critical care medicine.

[14]  S. Reddy,et al.  Nrf2 defends the lung from oxidative stress. , 2006, Antioxidants & redox signaling.

[15]  G. Scheffer,et al.  Cytokines and biotrauma in ventilator-induced lung injury: a critical review of the literature. , 2005, The Netherlands journal of medicine.

[16]  C. Waters,et al.  Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[17]  G. Zimmerman,et al.  Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. , 2005, American journal of respiratory cell and molecular biology.

[18]  Stephanie Nonas,et al.  Bioinformatic identification of novel early stress response genes in rodent models of lung injury. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[19]  R. Glenny,et al.  Modulation of Lipopolysaccharide-Induced Gene Transcription and Promotion of Lung Injury by Mechanical Ventilation1 , 2005, The Journal of Immunology.

[20]  M. O’Reilly,et al.  Reactive oxidant and p42/44 MAP kinase signaling is necessary for mechanical strain-induced proliferation in pulmonary epithelial cells. , 2005, Journal of applied physiology.

[21]  R. Tuder,et al.  Inducible nitric oxide synthase contributes to ventilator-induced lung injury. , 2005, American journal of respiratory and critical care medicine.

[22]  R. Hubmayr,et al.  Cellular stress failure in ventilator-injured lungs. , 2005, American journal of respiratory and critical care medicine.

[23]  R. Irizarry,et al.  In vitro identification and in silico utilization of interspecies sequence similarities using GeneChip® technology , 2005, BMC Genomics.

[24]  M. Nishimura,et al.  Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. , 2005, Biological & pharmaceutical bulletin.

[25]  Irina Petrache,et al.  Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. , 2004, The Journal of clinical investigation.

[26]  S. Dower,et al.  Human Tribbles, a Protein Family Controlling Mitogen-activated Protein Kinase Cascades* , 2004, Journal of Biological Chemistry.

[27]  R. Glenny,et al.  Mechanical Ventilation with Moderate Tidal Volumes Synergistically Increases Lung Cytokine Response to Systemic Endotoxin Running Title: Mechanical Ventilation and Lps , 2022 .

[28]  Janet E. Holley,et al.  Pulmonary antioxidant concentrations and oxidative damage in ventilated premature babies , 2004, Archives of Disease in Childhood - Fetal and Neonatal Edition.

[29]  S. Reddy,et al.  The transcription factor NRF2 protects against pulmonary fibrosis , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  H. Rabb,et al.  Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. , 2004, American journal of respiratory and critical care medicine.

[31]  John Quackenbush,et al.  Orthologous gene-expression profiling in multi-species models: search for candidate genes , 2004, Genome Biology.

[32]  D. Quinn,et al.  Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase. , 2004, American journal of respiratory and critical care medicine.

[33]  T. Goldmann,et al.  Phosphoinositide 3-OH kinase inhibition prevents ventilation-induced lung cell activation. , 2004, American journal of respiratory and critical care medicine.

[34]  Janet S. Lee,et al.  Cytokine-mediated inflammation in acute lung injury. , 2003, Cytokine & growth factor reviews.

[35]  W. Schobersberger,et al.  Association of endogenous G-CSF with anti-inflammatory mediators in patients with acute respiratory distress syndrome. , 2003, Journal of Interferon and Cytokine Research.

[36]  C. McKerlie,et al.  Early changes in lung gene expression due to high tidal volume. , 2003, American journal of respiratory and critical care medicine.

[37]  R. Boucher,et al.  Effect of ventilatory rate on airway cytokine levels and lung injury. , 2003, The Journal of surgical research.

[38]  M. Burdick,et al.  Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. , 2002, The Journal of clinical investigation.

[39]  C. Deutschman,et al.  Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome. , 2002, The Journal of clinical investigation.

[40]  J. Fredberg,et al.  Cellular biomechanics in the lung. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[41]  V. Malhotra,et al.  ABLATION OF THE HEAT SHOCK FACTOR-1 INCREASES SUSCEPTIBILITY TO HYPEROXIA-MEDIATED CELLULAR INJURY , 2002, Experimental lung research.

[42]  W. MacNee,et al.  Oxidative stress and lung inflammation in airways disease. , 2001, European journal of pharmacology.

[43]  L. Ortiz,et al.  Effects of cigarette smoke in mice with different levels of alpha(1)-proteinase inhibitor and sensitivity to oxidants. , 2001, American journal of respiratory and critical care medicine.

[44]  S. Uhlig,et al.  Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids. , 2001, American journal of respiratory and critical care medicine.

[45]  D. Schoenfeld,et al.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. , 2000, The New England journal of medicine.

[46]  T. Evans,et al.  G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. , 2000, The European respiratory journal.

[47]  K. Steinberg,et al.  Modulation of neutrophil apoptosis by granulocyte colony‐stimulating factor and granulocyte/macrophage colony‐stimulating factor during the course of acute respiratory distress syndrome , 2000, Critical care medicine.

[48]  Peter M. Suter,et al.  Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. , 1999, JAMA.

[49]  M. J. Bragado,et al.  Purification and Characterization of a Novel Physiological Substrate for Calcineurin in Mammalian Cells* , 1998, The Journal of Biological Chemistry.

[50]  T. Evans,et al.  Reactive oxygen species in acute lung injury. , 1998, The European respiratory journal.

[51]  D. Tweardy,et al.  G‐CSF instillation into rat lungs mediates neutrophil recruitment, pulmonary edema, and hypoxia , 1998, Journal of leukocyte biology.

[52]  Arthur S Slutsky,et al.  Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. , 1997, The Journal of clinical investigation.

[53]  F. Chu,et al.  Neutrophil migration through preexisting holes in the basal laminae of alveolar capillaries and epithelium during streptococcal pneumonia. , 1995, Microvascular research.

[54]  C. Cross,et al.  Free radicals, antioxidants, and human disease: where are we now? , 1992, The Journal of laboratory and clinical medicine.

[55]  M. Matthay,et al.  Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. , 1991, The Journal of clinical investigation.

[56]  E. Chi,et al.  Effects of leukotriene B4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability. , 1989, The Journal of clinical investigation.

[57]  K. Morano,et al.  All in the family: atypical Hsp70 chaperones are conserved modulators of Hsp70 activity , 2007, Cell stress & chaperones.

[58]  N. Arima,et al.  Acute lung Injury in a healthy donor during mobilization of peripheral blood stem cells using granulocyte-colony stimulating factor alone. , 2005, Haematologica.

[59]  B. Han,et al.  Ventilator-induced lung injury: role of protein-protein interaction in mechanosensation. , 2005 .

[60]  G. Nieman,et al.  Alveolar instability causes early ventilator-induced lung injury independent of neutrophils. , 2004, American journal of respiratory and critical care medicine.

[61]  S. Reddy,et al.  Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. , 2002, American journal of respiratory cell and molecular biology.

[62]  D. Tschumperlin,et al.  Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude. , 2000, American journal of respiratory and critical care medicine.