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1 Department of Internal Medicine
2 the Botnar Center for Clinical Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
3
Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
Pulmonary oedema results from an imbalance between the forces driving fluid into the airspace and the biological mechanisms for its removal. In mice lacking the 
-subunit of the amiloride-sensitive sodium channel (ENaC(–/–)), impaired sodium transport-mediated lung liquid clearance at birth results in neonatal death. Transgenic expression of ENaC driven by a cytomegalovirus (CMV) promoter (ENaC(–/–)Tg+) rescues the lethal pulmonary phenotype, but only partially restores respiratory sodium transport in vitro. To test whether this may also be true in vivo, and to assess the functional consequences of this defect on experimental pulmonary oedema, we measured respiratory transepithelial potential difference (PD) and alveolar fluid clearance (AFC), and quantified pulmonary oedema during experimental acute lung injury in these mice. Both respiratory PD and AFC were roughly 50% lower (P < 0.01) in ENaC(–/–)Tg+ than in control mice. This impairment was associated with a significantly larger increase of the wet/dry lung weight ratio in ENaC(–/–)Tg+ than in control mice, both after exposure to hyperoxia and thiourea. Moreover, the rate of resolution of thiourea-induced pulmonary oedema was more than three times slower (P < 0.001) in ENaC(–/–)Tg+ mice. ENaC(–/–)Tg+ mice represent the first model of a constitutively impaired respiratory transepithelial sodium transport, and provide direct evidence that this impairment facilitates pulmonary oedema in conscious freely moving animals. These data in mice strengthen indirect evidence provided by clinical studies, suggesting that defective respiratory transepithelial sodium transport may also facilitate pulmonary oedema in humans.
(Received 19 April 2004;
accepted after revision 9 August 2004;
first published online 12 August 2004)
Corresponding author U. Scherrer: Department of Internal Medicine, BH 10.642, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. Email: urs.scherrer{at}hospvd.ch
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