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Review
. 1999 Feb;103(3):309-12.
doi: 10.1172/JCI6222.

The genesis of cystic fibrosis lung disease

J J Wine  1
Affiliations
Review

The genesis of cystic fibrosis lung disease

J J Wine. J Clin Invest. 1999 Feb.
No abstract available

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Figures

Figure 1
Figure 1
CFTR's multiple roles in fluid and electrolyte transport. (a) Salt absorption. In the sweat duct, high apical conductance for Na+ [1] and Cl– [2] and relatively low water conductance allows salt to be reabsorbed in excess of water (hypertonic absorption) leaving a hypotonic luminal fluid. In the sweat duct CFTR is the only available anion conductance pathway, and when it is lost in CF the lumen quickly becomes highly electronegative and transport virtually ceases, resulting in high (similar to plasma) luminal salt (b). Fluid absorption. In epithelia with high water permeability [3] relative to electrolyte permeability water will absorbed osmotically with salt to decrease the volume of luminal fluid. If no other osmolytes or forces are present, the salt concentration will remain unchanged. If water-retaining forces are present, permeant electrolytes can be reduced preferentially. The consequences of eliminating CFTR depend on the magnitude of such forces, the relative magnitude of alternate pathways for transepithelial anion flow [4], and how CFTR affects other ion channels. The high salt and low volume hypotheses differ on each of these points. (c) Anion-mediated fluid secretion. Secreting epithelia lack a significant apical Na+ conductance. Basolateral transporters such as NKCC move Cl– uphill into the cell; it then flows passively into the lumen via CFTR [5], K+ exits basolaterally, Na+ flows paracellularly [7] and water follows transcellularly [6]. Elimination of CFTR eliminates secretion.
Figure 2
Figure 2
Two hypotheses of how airway surface liquid (ASL) differs in healthy and CF lungs. (a) The high salt hypothesis (9, 10) postulates that normal ASL has low levels of salt as a result of salt absorption in excess of water (A1, left). Even though the epithelium is water permeable, salt is retained in thin surface films by some combination of surface tension (28) and impermeant osmolytes (10). In CF (A2), salt is poorly absorbed resulting in excessively salty ASL that disrupts natural mucosal antibiotics. Key features of the high salt model are: the lack of an appreciable shunt Cl– conductance, central importance of CFTR's channel role, no specific role for inhibition of ENaC by CFTR, and a switch from isotonic volume absorption to hypertonic salt absorption as the surface layer thins and traps residual water. (b) The low volume hypothesis (14) postulates that normal ASL (B1) has salt levels approximately equal to plasma. In CF (B2), the removal of CFTR's inhibition of ENaC results in abnormally elevated isotonic fluid absorption which depletes the ASL and leads to reduced mucociliary clearance. Key features of the low volume model are the parallel pathway for Cl– via shunt pathway(s) and inhibition of ENaC via CFTR.
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References

    1. Bals R, Weiner DJ, Wilson JM. The innate immune system in cystic fibrosis lung disease. J Clin Invest. 1999;103:303–307. - PMC - PubMed
    1. McWilliam AS, et al. Dendritic cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli. J Exp Med. 1996;184:2429–2432. - PMC - PubMed
    1. Egan M, et al. Defective regulation of outwardly rectifying Cl- channels by protein kinase A corrected by insertion of CFTR. Nature. 1992;358:581–584. - PubMed
    1. Stutts MJ, Rossier BC, Boucher RC. Cystic fibrosis transmembrane conductance regulator inverts protein kinase A-mediated regulation of epithelial sodium channel single channel kinetics. J Biol Chem. 1997;272:14037–14040. - PubMed
    1. Knowles MR, et al. Abnormal ion permeation through cystic fibrosis respiratory epithelium. Science. 1983;221:1067–1070. - PubMed

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