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Carbon Monoxide Protects against Ventilator-induced Lung Injury via PPAR- and Inhibition of Egr-1

¹ Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; ² Department of Anesthesiology and Critical Care Medicine, University Hospital Freiburg, Freiburg, Germany; ³ Center of Biological Imaging, and ⁴ Department of Critical Care Medicine and Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and ⁵ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

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{at}rics.bwh.harvard.edu

Rationale: 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.

Objectives: This study explores the mechanisms of CO-dependent protection in a mouse model of VILI.

Methods: 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.

Measurements and Main Results: 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)-, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO.

Conclusions: Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR- and inhibition of Egr-1.

Key Words: carbon monoxide • early growth response-1 • inflammation • peroxysome proliferator-activated receptor- • ventilator-induced lung injury

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Mechanical ventilation can cause inflammatory lung injury. The antiinflammatory properties of carbon monoxide may be exploited to reduce lung injury caused by mechanical ventilation. What This Study Adds to the Field Carbon monoxide protects against pulmonary inflammation in a murine model of ventilator-induced lung injury by specific antiinflammatory mechanisms, involving peroxisome proliferator-activated receptor- and early growth response factor-1.

 

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