title: Carbon monoxide protects against ventilator-induced lung injury via PPAR-gamma and inhibition of Egr-1.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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)-gamma, 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-gamma and inhibition of Egr-1.
authors: Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors: Alexander
authors: A
authors: Hoetzel
authors: Tamas
authors: T
authors: Dolinay
authors: Simone
authors: S
authors: Vallbracht
authors: Yingze
authors: Y
authors: Zhang
authors: Hong Pyo
authors: HP
authors: Kim
authors: Emeka
authors: E
authors: Ifedigbo
authors: Sean
authors: S
authors: Alber
authors: A Murat
authors: AM
authors: Kaynar
authors: Rene
authors: R
authors: Schmidt
authors: Stefan W
authors: SW
authors: Ryter
authors: Augustine M K
authors: AM
authors: Choi
mesh_terms: D000403:Airway Resistance / Q000502:physiology; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D002248:Carbon Monoxide / Q000627:therapeutic use*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology; D012121:Respiration, Artificial / Q000009:adverse effects*; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000963:Antimetabolites; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D047495:PPAR gamma; D002248:Carbon Monoxide