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Published ahead of print on March 20, 2008, doi:10.1164/rccm.200708-1265OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 11, June 2008, 1223-1232

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Submitted on August 28, 2007
Accepted on March 20, 2008

Carbon Monoxide Protects Against Ventilator-Induced Lung Injury via PPAR-{gamma} and Inhibition of Egr-1

Alexander Hoetzel1, Tamas Dolinay2, Simone Vallbracht3, Yingze Zhang2, Hong Pyo Kim2, Emeka Ifedigbo2, Sean Alber4, A. Murat Kaynar5, Rene Schmidt3, Stefan W Ryter2, and Augustine MK Choi6*

1 Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Anaesthesiology and Critical Care Medicine, University Hospital Freiburg, Freiburg, Germany, 2 Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 3 Department of Anaesthesiology and Critical Care Medicine, University Hospital Freiburg, Freiburg, Germany, 4 Center for Biological Imaging, University of Pittsburgh Medical Center, Pittsburgh, PA, USA, 5 Department of Critical Care Medicine and Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA, 6 Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: amchoi{at}rics.bwh.harvard.edu.

Rationale: Ventilator-induced lung injury leads to an unacceptably high mortality. In this regard, the anti-inflammatory properties of inhaled carbon monoxide may provide a therapeutic option. Objectives: This study explores the mechanisms of carbon monoxide-dependent protection in a mouse model of ventilator-induced lung injury. Methods: Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of carbon monoxide (250 parts per million). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury and gene expression. Bronchoalveolar lavage was analyzed for protein, cell and neutrophil counts, and cytokines. 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, carbon monoxide application prevented lung injury during ventilation, inhibited stress-gene upregulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilationinduced cytokine and chemokine production. Furthermore, carbon monoxide prevented the early ventilation-dependent upregulation 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 pro-inflammatory regulator in ventilator-induced lung injury. Moreover, inhibition of peroxysome proliferator-activated receptor-{gamma} (PPAR-{gamma}), an anti-inflammatory nuclear regulator, by GW9662, abolished the protective effects of carbon monoxide. Conclusion: Mechanical ventilation causes profound lung injury and inflammatory responses. Carbon monoxide treatment conferred protection in this model dependent on PPAR-{gamma} and inhibition of Egr-1.
Key words: Carbon monoxide, Early growth response-1, Inflammation, Peroxysome proliferator-activated receptor-{gamma} , Ventilator-induced lung injury




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