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


OBJECTIVE
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.


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.
Papaiahgari
Srinivas
S
Department of Environmental Health Sciences/Division of Physiology, Room E7547, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Yerrapureddy
Adi
A
Reddy
Swetha R
SR
Reddy
Narsa M
NM
Dodd-O
Jeffery M
JM
Crow
Michael T
MT
Grigoryev
Dimitry N
DN
Barnes
Kathleen
K
Tuder
Rubin M
RM
Yamamoto
Masayuki
M
Kensler
Thomas W
TW
Biswal
Shyam
S
Mitzner
Wayne
W
Hassoun
Paul M
PM
Reddy
Sekhar P
SP
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D012122:Ventilators, Mechanical / Q000009:adverse effects*
D000975:Antioxidants; D016207:Cytokines; D016166:Free Radical Scavengers; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000111:Acetylcysteine