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1 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
2 Department of Anesthesia, University of California, San Francisco, San Francisco, CA, USA
3 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Anesthesia, University of California, San Francisco, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: frankja{at}itsa.ucsf.edu.
Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome (ARDS). To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal airspace edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg), or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal airspace fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1h of high tidal volume, but returned to the pre-ventilation rate 2h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung NOS2 expression and airspace total nitrite at 3h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because airspace edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.
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