β-Liddle mutation of the epithelial sodium channel increases alveolar fluid clearance and reduces the severity of hydrostatic pulmonary oedema in mice
- 5 July 2007
- journal article
- Published by Wiley in The Journal of Physiology
- Vol. 582 (2), 777-788
- https://doi.org/10.1113/jphysiol.2007.131078
Abstract
Transepithelial sodium transport via alveolar epithelial Na(+) channels and Na(+),K(+)-ATPase constitutes the driving force for removal of alveolar oedema fluid. Decreased activity of the amiloride-sensitive epithelial Na(+) channel (ENaC) in the apical membrane of alveolar epithelial cells impairs sodium-driven alveolar fluid clearance (AFC) and predisposes to pulmonary oedema. We hypothesized that hyperactivity of ENaC in the distal lung could improve AFC and facilitate the resolution of pulmonary oedema. AFC and lung fluid balance were studied at baseline and under conditions of hydrostatic pulmonary oedema in the beta-Liddle (L) mouse strain harbouring a gain-of-function mutation (R(566)(stop)) within the Scnn1b gene. As compared with wild-type (+/+), baseline AFC was increased by 2- and 3-fold in heterozygous (+/L) and homozygous mutated (L/L) mice, respectively, mainly due to increased amiloride-sensitive AFC. The beta(2)-agonist terbutaline stimulated AFC in +/+ and +/L mice, but not in L/L mice. Acute volume overload induced by saline infusion (40% of body weight over 2 h) significantly increased extravascular (i.e. interstitial and alveolar) lung water as assessed by the bloodless wet-to-dry lung weight ratio in +/+ and L/L mice, as compared with baseline. However, the increase was significantly larger in +/+ than in L/L groups (P=0.01). Volume overload also increased the volume of the alveolar epithelial lining fluid in +/+ mice, indicating the presence of alveolar oedema, but not in L/L mice. Cardiac function as evaluated by echocardiography was comparable in both groups. These data show that constitutive ENaC activation improved sodium-driven AFC in the mouse lung, and attenuated the severity of hydrostatic pulmonary oedema.Keywords
This publication has 48 references indexed in Scilit:
- RNA interference for α-ENaC inhibits rat lung fluid absorption in vivoAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2006
- Temporally Controlled Onset of Dilated Cardiomyopathy Through Disruption of the SRF Gene in Adult HeartCirculation, 2005
- Discovery of Glycine Hydrazide Pore-occluding CFTR InhibitorsThe Journal of general physiology, 2004
- Alveolar Type 1 Cells Express the α2 Na,K-ATPase, Which Contributes to Lung Liquid ClearanceCirculation Research, 2003
- Hypoxia and β2-Agonists Regulate Cell Surface Expression of the Epithelial Sodium Channel in Native Alveolar Epithelial CellsPublished by Elsevier BV ,2002
- Adenovirus-Mediated Transfer of an Na+/K+-ATPase β1Subunit Gene Improves Alveolar Fluid Clearance and Survival in Hyperoxic RatsHuman Gene Therapy, 2000
- Liddle’s syndrome mutations disrupt cAMP-mediated translocation of the epithelial Na+ channel to the cell surfaceJCI Insight, 2000
- Augmentation of lung liquid clearance via adenovirus-mediated transfer of a Na,K-ATPase beta1 subunit gene.JCI Insight, 1998
- Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry.The Journal of cell biology, 1994
- Stimulation of lung epithelial liquid clearance by endogenous release of catecholamines in septic shock in anesthetized rats.JCI Insight, 1994