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Published ahead of print on July 28, 2004, doi:10.1164/rccm.200405-684OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 9, November 2004, 987-993

A more recent version of this article appeared on November 1, 2004
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Submitted on June 2, 2004
Accepted on July 23, 2004

Sphingosine 1-Phosphate Reduces Vascular Leak in Murine and Canine Models of Acute Lung Injury

Bryan J McVerry1, Xinqi Peng1, Paul M Hassoun1, Saad Sammani1, Brett A Simon2, and Joe G.N. Garcia1*

1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Center for Translational Respiratory Medicine, Baltimore, MD, USA, 2 Department of Anesthesia and Critical Care Medicine, Johns Hopkins University School of Medicine, Center for Translational Respiratory Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: drgarcia{at}jhmi.edu.

Excessive mechanical stress is a key component of ventilator-associated lung injury resulting in profound vascular leak and an intense inflammatory response. To extend our in vitro observations concerning the barrier-protective effects of the lipid growth factor, sphingosine 1-phosphate, we assessed the ability of sphingosine 1-phosphate to prevent regional pulmonary edema accumulation in clinically relevant rodent and canine models of acute lung injury induced by combined intrabronchial endotoxin administration and high tidal volume mechanical ventilation. Intravenously delivered sphingosine 1-phosphate significantly attenuated both alveolar and vascular barrier dysfunction, while significantly reducing shunt formation associated with lung injury. Whole lung computed tomographic image analysis demonstrated the capability of sphingosine 1-phosphate to significantly abrogate the accumulation of extravascular lung water evoked by 6-hour exposure to endotoxin. Axial density profiles and vertical density gradients localized the sphingosine 1-phosphate response to transitional zones between aerated and consolidated lung regions. Together, these results indicate that sphingosine 1-phosphate represents a novel therapeutic intervention for the prevention of pulmonary edema related to inflammatory injury and increased vascular permeability.
Key words: acute lung injury, mechanical ventilation, endothelial permeability, CT imaging




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