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Trendsetters

Altered NaCl Concentration of Airway Surface Liquid in Cystic Fibrosis

Jonathan H. Widdicombe

Children's Hospital Oakland Research Institute 747 52nd Street Oakland, CA 94609–1809
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.

Heinz Valtin

Editor,TRENDSETTERS

The major pathology in cystic fibrosis (CF) results from the colonization of the airways by the bacterium Pseudomonas aeruginosa. Indirect evidence suggests that this colonization occurs because the thin (10 µm) film of liquid that lines the airways (so-called airway surface liquid; Fig. 1) is saltier in CF patients than in healthy individuals and the endogenous antibiotics that are secreted by the respiratory epithelium are better able to kill bacteria in comparatively dilute medium (1).

View larger version (38K): [in this window] [in a new window]   FIGURE 1. Schematic representation of airway epithelium during healthy conditions and during cystic fibrosis. The solid downward arrow denotes active Na transport. The two dashed arrows denote passive transport of Cl, with by far the larger portion being transcellular (heavy dashed arrow) and the minor portion being paracellular (lighter dashed arrow). In cystic fibrosis, the transcellular pathway for Cl is effectively absent, and absorption of Cl is reduced. The demands of electroneutrality result in an equivalent reduction in active absorption of Na.

To explain this striking change in CF, we must first ask how the NaCl concentration of airway surface liquid is normally held at values so much lower than those in the medium bathing the basolateral side (Fig. 1). The primary process that removes salt from the airway surface liquid is active absorption of Na. This creates a transepithelial potential difference of ~30 mV (lumen negative), which drives the passive movement of anions, mainly Cl, that accompany the Na and maintain electroneutrality. Why doesn't water follow the absorbed NaCl down the resulting osmotic gradient? Or put differently, Why is the absorbate apparently so hypertonic? A low osmotic permeability of airway epithelium would provide the answer, but this does not seem to be the case. An untested possibility is that the absorption of NaCl is balanced by secretion (into the apical medium) of some unknown osmolyte. Another possibility is that when the film of airway surface liquid becomes sufficiently thin, the structures on the apical (airway) surface (cilia, microvilli, mucus gel) generate surface tension forces that prevent the osmotic flow of water.

The next question is, Why are the Na and Cl concentrations of airway surface liquid elevated in CF? The answer may lie in recent research indicating that a substantial fraction of the Cl that follows the actively absorbed Na passes through rather than between the cells (2), a route that involves the cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in CF. Thus, in cultures of bovine tracheal epithelium, the use of microelectrodes revealed that the net electrochemical driving forces for Cl movement were inward across the apical membrane (i.e., from apical surface liquid into the cell) and outward across the basolateral membrane (i.e., from the cell into the interstitium). Patch-clamp studies showed that both the apical and basolateral cell membranes contained cAMP-activated Cl channels. In the apical membrane the predominant channel was CFTR, but the channel in the basolateral membrane had a biophysical signature quite distinct from CFTR. The following experiment illustrates that this transcellular pathway can be activated physiologically. The apical surface of bovine cell sheets was bathed in a large volume of liquid. Under these circumstances (as opposed to when airway surface liquid is present as a thin film held in place by surface tension), the epithelium could absorb isotonic NaCl solution and opening of apical and basolateral Cl channels by elevation of intracellular cAMP resulted in a threefold increase in transepithelial fluid absorption.

In summary, in CF lack of functional CFTR in the apical membrane will block the transcellular route for Cl absorption (indicated in Fig. 1 by the heavy dashed arrow). When CF tissues are bathed with a large volume of apical medium, this will result in lower than normal rates of isotonic saline absorption, as has recently been reported (3). When the airway surface liquid is present as a thin film of set volume, the reduced ability of Cl to pass through the cells will inhibit removal of NaCl from this film and promote the higher than normal levels of Na and Cl found in airway surface liquid in CF (3).

References

1. Smith, J. J., S. M. Travis, E. P. Greenberg, and M. J. Welsh. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 85: 229–236, 1996.[Medline]
2. Uyekubo, S. N., H. Fischer, A. Maminishkis, S. S. Miller, and J. H. Widdicombe. Cyclic AMP-dependent absorption of chloride across airway epithelium. Am. J. Physiol. 275 (Lung Cell. Mol. Physiol. 19): L1219–L1227, 1998.[Abstract/Free Full Text]
3. Zabner, J., J. J. Smith, P. H. Karp, J. H. Widdicombe, and M. J. Welsh. Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro. Mol. Cell. 2: 397–403, 1998.[Medline]

Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only.

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