Article: article from journal or magazin.
Novel role for CFTR in fluid absorption from the distal airspaces of the lung.
Journal of General Physiology
Publication types: Comparative Study ; In Vitro ; Journal Article
The active absorption of fluid from the airspaces of the lung is important for the resolution of clinical pulmonary edema. Although ENaC channels provide a major route for Na(+) absorption, the route of Cl(-) transport has been unclear. We applied a series of complementary approaches to define the role of Cl(-) transport in fluid clearance in the distal airspaces of the intact mouse lung, using wild-type and cystic fibrosis Delta F508 mice. Initial studies in wild-type mice showed marked inhibition of fluid clearance by Cl(-) channel inhibitors and Cl(-) ion substitution, providing evidence for a transcellular route for Cl(-) transport. In response to cAMP stimulation by isoproterenol, clearance was inhibited by the CFTR inhibitor glibenclamide in both wild-type mice and the normal human lung. Although isoproterenol markedly increased fluid absorption in wild-type mice, there was no effect in Delta F508 mice. Radioisotopic clearance studies done at 23 degrees C (to block active fluid absorption) showed approximately 20% clearance of (22)Na in 30 min both without and with isoproterenol. However, the clearance of (36)Cl was increased by 47% by isoproterenol in wild-type mice but was not changed in Delta F508 mice, providing independent evidence for involvement of CFTR in cAMP-stimulated Cl(-) transport. Further, CFTR played a major role in fluid clearance in a mouse model of acute volume-overload pulmonary edema. After infusion of saline (40% body weight), the lung wet-to-dry weight ratio increased by 28% in wild-type versus 64% in Delta F508 mice. These results provide direct evidence for a functionally important role for CFTR in the distal airspaces of the lung.
Absorption/physiology, Animals, Bronchodilator Agents/pharmacology, Chloride Channels/antagonists &, inhibitors, Chloride Channels/metabolism, Cystic Fibrosis/genetics, Cystic Fibrosis/metabolism, Cystic Fibrosis Transmembrane Conductance Regulator/antagonists &, inhibitors, Cystic Fibrosis Transmembrane Conductance Regulator/genetics, Humans, Isotonic Solutions/pharmacokinetics, Lung/drug effects, Lung/physiology, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Pulmonary Edema/genetics, Pulmonary Edema/metabolism, Sodium Chloride/metabolism
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