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Comparative Study
. 2002 Feb;119(2):199-207.
doi: 10.1085/jgp.119.2.199.

Novel role for CFTR in fluid absorption from the distal airspaces of the lung

X Fang  1 , N Fukuda, P Barbry, C Sartori, A S Verkman, M A Matthay
Affiliations
Comparative Study

Novel role for CFTR in fluid absorption from the distal airspaces of the lung

X Fang et al. J Gen Physiol. 2002 Feb.

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.

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Figures

F<sc>igure</sc> 1.
Figure 1.
Effect of amiloride, NPPB, and ouabain on isosmolar fluid clearance at 37°C in the in situ nonperfused lung of wild-type mice. Fluid clearance is expressed as the percent fluid absorption at 15 min (n = 6–8 mice in each group). Where indicated, the instillate contained 1 mM amiloride, 0.1 mM NPPB, or 0.1 mM ouabain. *P < 0.05 compared with control, data as mean ± SEM.
F<sc>igure</sc> 2.
Figure 2.
Effect of ion substitution on isosmolar fluid clearance from the distal airspaces. Experiments were done in the in situ perfused lung at 37°C in wild-type mice. The x-axis indicates the composition of the test solutions. Measurements were done under basal (open bars, n = 6 mice in each group) and isoproterenol stimulated (closed bars, n = 6 in each group) conditions. *P < 0.05 compared with all other control conditions; **P < 0.05 compared with basal in each group, data as mean ± SEM.
F<sc>igure</sc> 3.
Figure 3.
Effect of glibenclamide on fluid clearance in mouse and human lung. (A) Fluid clearance in the in situ perfused lung of wild-type mice at 37°C. Fluid clearance is expressed as the percent absorption at 15 min under control conditions (n = 12), glibenclamide (0.1 mM, n = 6), isoproterenol (0.1 mM, n = 18), and isoproterenol + glibenclamide (n = 6). *P < 0.05 compared with control, data as mean ± SEM. (B) Measurements of fluid clearance in rewarmed ex vivo human lung at 37°C. Fluid clearance is expressed as the percent absorption at 1 h under control conditions (n = 23), glibenclamide (0.1 mM, n = 5), terbutaline (0.1 mM, n = 8), and terbutaline + glibenclamide (n = 6). *P < 0.05 compared with control, data as mean ± SEM.
F<sc>igure</sc> 4.
Figure 4.
Fluid clearance from the distal airspaces of wild-type (open bars) and ΔF508 (closed bars) mice. Measurements were done in the in situ perfused lung at 37°C under basal conditions (n = 24 wild-type, n = 7 ΔF508) and in the presence of 0.1 mM isoproterenol (n = 9 wild-type, n = 6 ΔF508). *P < 0.05 compared with control group, data as mean ± SEM.
F<sc>igure</sc> 5.
Figure 5.
Isotopic 22Na and 36Cl transport from the airspace compartment of wild-type and ΔF508 mice. Measurements were done in the in situ perfused lung preparation at 23°C. The y-axis is the ratio of final (30 min after instillation) to initial (1 min after instillation) 22Na or 36Cl radioactivities in fluid sampled from the distal airspaces. Individual (closed circles) and averaged (mean ± SEM) values are shown. Where indicated, the instillate contained 0.1 mM isoproterenol (iso), 0.1 mM glibenclamide (glib), and 0.1 mM isoproterenol + 0.1 mM glibenclamide. *P < 0.05 compared with all other groups.
F<sc>igure</sc> 6.
Figure 6.
Effect of acute volume overload on the lung wet-to-dry weight ratio in wild-type, heterozygous, and ΔF508 mice. 40% of body weight fluid was infused over 2 h (materials and methods). The y-axis is the lung wet-to-dry weight ratio. Individual (closed) and averaged (mean ± SEM) values are shown for indicated genotypes of mice. In the volume-overload group, where indicated, measurements were performed with and without propranolol (0.1 mM) pretreatment. (*P < 0.05 compared with basal control; **P < 0.05 compared with wild-type and heterozygous mice in the same group. [Insets] Micrographs show typical lung histopathology from three different groups, as indicated with the dashed lines). Normal distal airway and alveolar structure in control ventilated wild-type mice not subjected to volume overload (left). Thickening of interstitial space and perivascular fluid cuffs (arrow) in volume-overloaded wild-type mice (middle). Alveolar edema in most sections of volume-overloaded ΔF508 mice (right). Bar, 30 μm.
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