Novel Role for CFTR in Fluid Absorption from the Distal Airspaces of the Lung

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 ΔF508 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 ΔF508 mice. Radioisotopic clearance studies done at 23°C (to block active fluid absorption) showed ∼20% clearance of ²²Na in 30 min both without and with isoproterenol. However, the clearance of ³⁶Cl was increased by 47% by isoproterenol in wild-type mice but was not changed in ΔF508 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 ΔF508 mice. These results provide direct evidence for a functionally important role for CFTR in the distal airspaces of the lung.