title: Novel role for CFTR in fluid absorption from the distal airspaces of the lung.
abstract: 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.
authors.affiliation: Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: X
authors.initials: X
authors.lastname: Fang
authors.forename: N
authors.initials: N
authors.lastname: Fukuda
authors.forename: P
authors.initials: P
authors.lastname: Barbry
authors.forename: C
authors.initials: C
authors.lastname: Sartori
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: M A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000042:Absorption / Q000502:physiology; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007552:Isotonic Solutions / Q000493:pharmacokinetics*; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011654:Pulmonary Edema / Q000235:genetics / Q000378:metabolism; D012965:Sodium Chloride / Q000378:metabolism
chemical_list: D001993:Bronchodilator Agents; C505032:CFTR protein, human; D018118:Chloride Channels; D007552:Isotonic Solutions; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012965:Sodium Chloride