Augmentation of lung liquid clearance via adenovirus-mediated transfer of a Na,K-ATPase beta1 subunit gene.
Previous studies have suggested that alveolar Na,K-ATPases play an important role in active Na+ transport and lung edema clearance. We reasoned that overexpression of Na,K-ATPase subunit genes could increase Na,K-ATPase function in lung epithelial cells and edema clearance in rat lungs. To test this hypothesis we produced replication deficient human type 5 adenoviruses containing cDNAs for the rat alpha1 and beta1 Na,K-ATPase subunits (adMRCMValpha1 and adMRCMVbeta1, respectively). As compared to controls, adMRCMVbeta1 increased beta1 subunit expression and Na,K-ATPase function by 2. 5-fold in alveolar type 2 epithelial cells and rat airway epithelial cell monolayers. No change in Na,K-ATPase function was noted after infection with adMRCMValpha1. Rat lungs infected with adMRCMVbeta1, but not adMRCMValpha1, had increased beta1 protein levels and lung liquid clearance 7 d after tracheal instillation. Alveolar epithelial permeability to Na+ and mannitol was mildly increased in animals infected with adMRCMVbeta1 and a similar Escherichia coli lacZ-expressing virus. Our data shows, for the first time, that transfer of the beta1 Na,K-ATPase subunit gene augments Na,K-ATPase function in epithelial cells and liquid clearance in rat lungs. Conceivably, overexpression of Na,K-ATPases could be used as a strategy to augment lung liquid clearance in patients with pulmonary edema.
Factor
P
P
Section of Pulmonary and Critical Care Medicine, Michael Reese Hospital, Chicago, Illinois 60616, USA. pfact@aol.com
Saldias
F
F
Ridge
K
K
Dumasius
V
V
Zabner
J
J
Jaffe
H A
HA
Blanco
G
G
Barnard
M
M
Mercer
R
R
Perrin
R
R
Sznajder
J I
JI
D000260:Adenoviruses, Human; D000818:Animals; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D008168:Lung / Q000166:cytology / Q000502:physiology*; D046911:Macromolecular Substances; D008297:Male; D011650:Pulmonary Alveoli / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D011654:Pulmonary Edema / Q000628:therapy*; D011663:Pulmonary Surfactants / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis / Q000235:genetics*
D046911:Macromolecular Substances; D011663:Pulmonary Surfactants; D011994:Recombinant Proteins; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase