Defective respiratory amiloride-sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice.
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 alpha-subunit of the amiloride-sensitive sodium channel (alphaENaC(-/-)), impaired sodium transport-mediated lung liquid clearance at birth results in neonatal death. Transgenic expression of alphaENaC driven by a cytomegalovirus (CMV) promoter (alphaENaC(-/-)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 alphaENaC(-/-)Tg+ than in control mice. This impairment was associated with a significantly larger increase of the wet/dry lung weight ratio in alphaENaC(-/-)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 alphaENaC(-/-)Tg+ mice. alphaENaC(-/-)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.
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.
Marc
M
Egli
Hervé
H
Duplain
Mattia
M
Lepori
Stéphane
S
Cook
Pascal
P
Nicod
Edith
E
Hummler
Claudio
C
Sartori
Urs
U
Scherrer
D000584:Amiloride; D000818:Animals; D053503:Epithelial Sodium Channels; D020022:Genetic Predisposition to Disease; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011654:Pulmonary Edema / Q000235:genetics* / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D015222:Sodium Channels / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D000584:Amiloride