Opinion
Cystic fibrosis: a disease of vulnerability to airway surface dehydration

https://doi.org/10.1016/j.molmed.2007.05.001Get rights and content

Cystic fibrosis (CF) lung disease involves chronic bacterial infection of retained airway secretions (mucus). Recent data suggest that CF lung disease pathogenesis reflects the vulnerability of airway surfaces to dehydration and collapse of mucus clearance. This predisposition is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in (i) the absence of CFTR-mediated Cl secretion and regulation of epithelial Na+ channel (ENaC) function; and (ii) the sole dependence on extracellular ATP to rebalance these ion transport processes through P2 purinoceptor signaling. Recent clinical studies indicate that inhalation of hypertonic saline osmotically draws sufficient water onto CF airway surfaces to provide clinical benefit.

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

References (71)

  • W.C. Watt

    Cystic fibrosis transmembrane regulator-independent release of ATP. Its implications for the regulation of P2Y2 receptors in airway epithelia

    J. Biol. Chem.

    (1998)
  • S.F. Okada

    Physiological regulation of ATP release at the apical surface of human airway epithelia

    J. Biol. Chem.

    (2006)
  • S.H. Abman

    Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis

    J. Pediatr.

    (1988)
  • J.F. Tomashefski

    Pulmonary air cysts in cystic fibrosis: relation of pathologic features to radiologic findings and history of pneumothorax

    Hum. Pathol.

    (1985)
  • F.R. Long

    Structural airway abnormalities in infants and young children with cystic fibrosis

    J. Pediatr.

    (2004)
  • C.M.P. Ribeiro

    Cystic fibrosis airway epithelial Ca2+i signalling. The mechanism for the larger agonist-mediated Ca2+i signals in human cystic fibrosis airway epithelia

    J. Biol. Chem.

    (2005)
  • K. Mori

    Tripartite management of unfolded proteins in the endoplasmic reticulum

    Cell

    (2000)
  • C. Patil et al.

    Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals

    Curr. Opin. Cell Biol.

    (2001)
  • E.Y. Chen

    The ΔF508 mutation disrupts packing of the transmembrane segments of the cystic fibrosis transmembrane conductance regulator

    J. Biol. Chem.

    (2004)
  • P.L. Zeitlin

    A phase I trial of intranasal Moli1901 for cystic fibrosis

    Chest

    (2004)
  • J.R. Riordan

    Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

    Science

    (1989)
  • B. Kerem

    Identification of the cystic fibrosis gene: genetic analysis

    Science

    (1989)
  • J.R. Riordan

    Assembly of functional CFTR chloride channels

    Annu. Rev. Physiol.

    (2005)
  • W.B. Guggino et al.

    New insights into cystic fibrosis: molecular switches that regulate CFTR

    Nat. Rev. Mol. Cell Biol.

    (2006)
  • P.B. Davis

    Cystic fibrosis since 1938

    Am. J. Respir. Crit. Care Med.

    (2006)
  • A. Perez

    CFTR inhibition mimics the cystic fibrosis inflammatory profile

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (2007)
  • M.N. Becker

    Cytokine secretion by cystic fibrosis airway epithelial cells

    Am. J. Respir. Crit. Care Med.

    (2004)
  • G.B. Pier

    Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections

    Science

    (1996)
  • M.R. Knowles

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

    J. Clin. Invest.

    (1997)
  • C. Kotaru

    Desiccation and hypertonicity of the airway surface fluid and thermally induced asthma

    J. Appl. Physiol.

    (2003)
  • A.S. Verkman

    Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease

    Am. J. Physiol. Cell Physiol.

    (2003)
  • Y. Song

    Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis

    Am. J. Physiol. Cell Physiol.

    (2006)
  • J.V. Wu

    Acinar origin of CFTR-dependent airway submucosal gland fluid secretion

    Am J Physiol Lung Cell Mol. Physiol

    (2007)
  • J.J. Wine et al.

    Submucosal glands and airway defense

    Proc. Am. Thorac. Soc.

    (2004)
  • S.K. Inglis et al.

    Cystic fibrosis and airway submucosal glands

    Pediatr. Pulmonol.

    (2005)
  • Cited by (213)

    • Small-molecule drugs for cystic fibrosis: Where are we now?

      2022, Pulmonary Pharmacology and Therapeutics
    View all citing articles on Scopus
    View full text