Article: article from journal or magazin.
beta-Liddle mutation of the epithelial sodium channel increases alveolar fluid clearance and reduces the severity of hydrostatic pulmonary oedema in mice
Journal of Physiology
Journal Article Research Support, Non-U.S. Gov't --- Old month value: Jul 15
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.
Adrenergic beta-Agonists/pharmacology Amiloride/pharmacology Animals Body Fluids/*metabolism Bronchi/metabolism Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors Diuretics/pharmacology Epithelial Sodium Channel/*genetics/metabolism Glycine/analogs & derivatives/pharmacology Heart/physiopathology Hydrostatic Pressure Lung/pathology Mice Mice, Mutant Strains Mice, Transgenic *Mutation Protein Isoforms/metabolism Pulmonary Alveoli/drug effects/*metabolism Pulmonary Edema/genetics/pathology/*physiopathology Severity of Illness Index Terbutaline/pharmacology
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