Trends in Molecular Medicine
OpinionCystic fibrosis: a disease of vulnerability to airway surface dehydration
Section snippets
Difficulties in translating mutations in CFTR into pathogenesis in CF lung disease
Research into the molecular pathogenesis of the syndrome of cystic fibrosis (CF) has evolved rapidly over the past 15 years. The identification and cloning of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) (see Glossary) protein was a seminal event in this evolution 1, 2. Subsequently, the molecular and cellular pathogenesis of the most common CFTR mutation, ΔF508 CFTR, and other common severe CFTR mutations, was demonstrated to result in a failure of the
Mechanical (mucus) clearance as the primary innate defense mechanism for airways
As shown in Figure 1, the effective clearance of particles deposited on airway surfaces requires the coordinated activities of a two-phase gel system on the airway surface: (i) the periciliary layer that extends from the cell surface to the height of the extended cilium; and (ii) the mucus layer that is positioned atop the cilia [24]. The layer that surrounds the cilia was originally thought to be a liquid but is more likely to be a grafted polyanionic gel [25]. Intriguingly, the properties of
Evidence for ASL volume depletion in CF
Evidence emanating from three systems favoring the low volume and dehydration hypothesis can be summarized as follows. First, observations from air–liquid interface cultures maintained under static conditions have demonstrated that normal airway epithelia maintain adequate ASL volume on airway surfaces (defined as liquid height being equal to the extended cilium – i.e. ∼7 μm) for extended periods of time, whereas CF cultures do not 22, 32 (Figure 1c,d). Bioelectric studies revealed that the
‘Key caveats’ to the notion of Na+ hyperabsorption and failed Cl− secretion in the pathogenesis of CF airways dehydration
Recent studies have suggested that the notion of simple, persistent Na+ hyperabsorption, coupled with failure to secrete Cl−, is an oversimplified version of what might happen in the CF patient [32]. Indeed, these studies were stimulated by predictions from in vitro studies (see earlier) that CF airways should rapidly and homogeneously fill with a mucus gel soon after birth, in contrast to the clinical data that demonstrated that CF airways disease becomes manifest many months to years after
Events ‘downstream’ of ASL volume depletion in CF airways pathogenesis
What is unique about the CF bacterial bronchitis phenotype is the persistence of the bacterial infection. For example, CF patients can be infected virtually life-long with the original Pseudomonas organism that colonizes and infects their lungs [51]. The acquisition of this persistent infection and the responses to it are complex but many aspects seem to be congruent with the dehydrated, adherent mucus plaques predicted by the low volume hypothesis.
One reason for CF airways infections being so
Therapies directed at airway surface rehydration in CF
Mammalian airway surfaces are relatively permeable to water [65]. Thus, rehydration therapies require the addition of salt to airway surfaces, to draw water onto airway surfaces osmotically. In general, there are two ways to ‘add salt’ to CF airway surfaces. The first is for patients to inhale HS (see earlier). The second is to administer agents to the CF airway surface that will redirect ion transport towards the secretory direction.
As described earlier, HS seems to have a therapeutic benefit
Concluding remarks
Data derived from multiple experimental systems suggest that CF airways are vulnerable to dehydration-induced loss of mechanical (mucus) clearance of airway surfaces. The dehydration that characterizes CF airway surfaces reflects the inability to regulate Na+ and Cl− transport coordinately owing to the absence of the CFTR function in the apical membrane of airway epithelia. New directions of research to understand this proximate component of CF airways disease pathogenesis should involve
Glossary
- Airway surface liquid (ASL)
- the water contained in the periciliary and mucus layers.
- Cystic fibrosis transmembrane conductance regulator (CFTR)
- protein product of the CFTR gene that exhibits, as its name implies, Cl− channel and ENaC regulatory properties.
- Epithelial Na+ channel (ENaC)
- heteromultimeric Na+ channel composed of products of three or four separate genes, including α, β, γ and, possibly, ς ENaC.
- Mucus layer
- layer composed of unrestrained secreted mucins in tangled networks interacting with
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