The discovery of mechanisms that regulate salt and water transport by the alveolar and distal airway epithelium of the lung has generated new insights into the regulation of lung fluid balance under both normal and pathological conditions. There is convincing evidence that active sodium and chloride transporters are expressed in the distal lung epithelium and are responsible for the ability of the lung to remove alveolar fluid at the time of birth as well as in the mature lung when pathological conditions lead to the development of pulmonary edema. Currently, the best described molecular transporters are the epithelial sodium channel, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and several aquaporin water channels. Both catecholamine-dependent and -independent mechanisms can upregulate isosmolar fluid transport across the distal lung epithelium. Experimental and clinical studies have made it possible to examine the role of these transporters in the resolution of pulmonary edema.

https://www.physiology.org/doi/pdf/10.1152/physrev.00003.2002

Lung epithelial fluid transport and the resolution of pulmonary edema.

Substantial progress has been made in understanding the role of the distal airway and alveolar epithelial barriers in regulating lung fluid balance. Molecular, cellular, and whole animal studies have demonstrated that reabsorption of fluid from the distal air spaces of the lung is driven by active sodium transport. Several different in vivo, in situ, and isolated lung preparations have been used to study the mechanisms that regulate fluid transport in the normal and injured lung. Catecholamine-dependent and -independent regulatory mechanisms have been identified that modulate fluid transport, probably by acting on apical sodium channel uptake or the activity of the Na, K-ATPase pumps. Recently, a family of molecular water channels (aquaporins) has been identified that are small (approximately 30 kDa) integral membrane proteins expressed widely in fluid-transporting epithelia and endothelia. At present, four different water channels have been identified in trachea and lung. Measurements of osmotic water permeability in in situ perfused lung and isolated perfused airways suggest a significant contribution of these molecular water channels to measured water permeability. However, further studies are required to determine the role of these water channels in normal pulmonary physiology and disease. Recent studies have provided new insights into the role of the alveolar epithelial barrier in clinical and experimental acute lung injury. Unlike the lung endothelium, the alveolar epithelium is resistant to several clinically relevant types of injury, including endotoxemia and bacteremia as well as aspiration of hyperosmolar solutions. In addition, even when the alveolar barrier has been injured, its capacity to transport edema fluid from the distal air spaces of the lung recovers rapidly. Future studies need to integrate new insights into the molecular mechanisms of alveolar epithelial sodium and water transport with functional studies in the normal and injured lung.

Salt and water transport across alveolar and distal airway epithelia in the adult lung.

To test whether a major contribution of airways epithelial ion transport to lung defense reflects the regulation of airway surface liquid (ASL) ionic composition, we measured ASL composition using the filter paper technique. On nasal surfaces, the Cl- concentration (approximately 125 meq/liter) was similar to plasma, but the Na+ concentration (approximately 110 meq/liter) was below plasma, and K+ concentration (approximately 30 meq/liter) above plasma. The resting ASL osmolarity [2(Na+ + K+); 277 meq/liter] approximated isotonicity. There were no detectable differences between cystic fibrosis (CF) and normal subjects. In the lower airways, the Na+ concentrations were 80-85 meq/liter, K+ levels approximately 15 meq/liter, and Cl- concentrations 75-80 meq/liter. Measurements of Na+ activity with Na(+)-selective electrodes and osmolality with freezing point depression yielded values consistent with the monovalent cation measurements. Like the nasal surfaces, no differences in cations were detected between CF, normal, or chronic bronchitis subjects. The tracheobronchial ASL hypotonicity was hypothesized to reflect collection-induced gland secretion, a speculation consistent with observations in which induction of nasal gland secretion produced hypotonic secretions. We conclude that there are no significant differences in ASL ion concentrations between CF, normal, and chronic bronchitis subjects and, because ASL ion concentrations exceed values consistent with defensin activity, the failure of CF lung defense may reflect predominantly factors other than salt-dependent defensins.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/119000/119802/JCI97119802.pdf

Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects.

Airway disease currently causes most of the morbidity and mortality in patients with cystic fibrosis (CF). However, understanding the pathogenesis of CF lung disease and developing novel therapeutic strategies have been hampered by the limitations of current models. Although the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) has been targeted in mice, CF mice fail to develop lung or pancreatic disease like that in humans. In many respects, the anatomy, biochemistry, physiology, size, and genetics of pigs resemble those of humans. Thus pigs with a targeted CFTR gene might provide a good model for CF. Here, we review aspects of porcine airways and lung that are relevant to CF.

The porcine lung as a potential model for cystic fibrosis.

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.

https://rupress.org/jgp/article-pdf/119/2/199/1216281/jgp1192199.pdf

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

Ion transport properties of pulmonary small airway epithelia are poorly understood. To characterize these properties, airways were excised from anesthetized pigs. Transepithelial potential differen...

A. E. Taylor

Papers

Regional bioelectric properties of porcine airway epithelium.