Carbon Monoxide Protects against Ventilator-induced Lung Injury via PPAR-γ and Inhibition of Egr-1
Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option. This study explores the mechanisms of CO-dependent protection in a mouse model of VILI. Mice were ventilate...
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Published in | American journal of respiratory and critical care medicine Vol. 177; no. 11; pp. 1223 - 1232 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York, NY
American Lung Association
01.06.2008
American Thoracic Society |
Subjects | |
Online Access | Get full text |
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Summary: | Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option.
This study explores the mechanisms of CO-dependent protection in a mouse model of VILI.
Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of CO (250 ppm). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury, and gene expression. Bronchoalveolar lavage fluid was analyzed for protein, cell and neutrophil counts, and cytokines.
Mechanical ventilation caused significant lung injury reflected by increases in protein concentration, total cell and neutrophil counts in the bronchoalveolar lavage fluid, as well as the induction of heme oxygenase-1 and heat shock protein-70 in lung tissue. In contrast, CO application prevented lung injury during ventilation, inhibited stress-gene up-regulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilation-induced cytokine and chemokine production. Furthermore, CO prevented the early ventilation-dependent up-regulation of early growth response-1 (Egr-1). Egr-1-deficient mice did not sustain lung injury after ventilation, relative to wild-type mice, suggesting that Egr-1 acts as a key proinflammatory regulator in VILI. Moreover, inhibition of peroxysome proliferator-activated receptor (PPAR)-gamma, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO.
Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-gamma and inhibition of Egr-1. |
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Bibliography: | Correspondence and requests for reprints should be addressed to Augustine M. K. Choi, M.D., Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail: amchoi@rics.bwh.harvard.edu Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200708-1265OC on March 20, 2008 Supported by a grant from the Deutsche Forschungsgemeinschaft to A.H. (DFG HO 2464/1-1); by an award from the American Heart Association to S.W.R., (AHA 0335035N) and H.P.K. (AHA 0525552 U); and NIH grants R01-HL60234, R01-HL55330, R01-HL079904, and P01-HL70807 awarded to A.M.K.C. |
ISSN: | 1073-449X 1535-4970 |
DOI: | 10.1164/rccm.200708-1265OC |