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

Publisher: American Thoracic Society Country of Publication: United States NLM ID: 9421642 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1535-4970 (Electronic) Linking ISSN: 1073449X NLM ISO Abbreviation: Am J Respir Crit Care Med Subsets: MEDLINE

Publication: 2000- : New York, NY : American Thoracic Society
Original Publication: New York, NY : American Lung Association, c1994-

Antioxidants/*metabolism ; NF-E2-Related Factor 2/*genetics ; Oxidative Stress/*drug effects ; Respiratory Distress Syndrome/*immunology ; Ventilators, Mechanical/*adverse effects; Acetylcysteine/pharmacology ; Animals ; Capillary Permeability/drug effects ; Capillary Permeability/physiology ; Cytokines/immunology ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Inflammation/prevention & control ; Male ; Mice ; Mice, Knockout ; Oxidative Stress/immunology ; Respiratory Distress Syndrome/drug therapy ; Respiratory Distress Syndrome/physiopathology

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.

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P50 HL073994 United States HL NHLBI NIH HHS

0 (Antioxidants)
0 (Cytokines)
0 (Free Radical Scavengers)
0 (NF-E2-Related Factor 2)
0 (Nfe2l2 protein, mouse)
WYQ7N0BPYC (Acetylcysteine)

Date Created: 20070929 Date Completed: 20071221 Latest Revision: 20220318

20221213

PMC2176106

10.1164/rccm.200701-060OC

17901416