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
References (71)
Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis
Cell
(1990)Chronic airway infection/inflammation induces a Ca2+i-dependent hyperinflammatory response in human cystic fibrosis airway epithelia
J. Biol. Chem.
(2005)Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid
Cell
(1996)Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro
Mol. Cell
(1998)Hyposecretion, not hyperabsorption, is the basic defect of cystic fibrosis airway glands
J. Biol. Chem.
(2006)Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease
Cell
(1998)The CF salt controversy: in vivo observations and therapeutic approaches
Mol. Cell
(2001)Normal and cystic fibrosis airway surface liquid homeostasis: the effects of phasic shear stress and viral infections
J. Biol. Chem.
(2005)Nucleotide release provides a mechanism for airway surface liquid homeostasis
J. Biol. Chem.
(2004)Metabolism of P2 receptor agonists in human airways: implications for mucociliary clearance and cystic fibrosis
J. Biol. Chem.
(2004)
Cystic fibrosis transmembrane regulator-independent release of ATP. Its implications for the regulation of P2Y2 receptors in airway epithelia
J. Biol. Chem.
Physiological regulation of ATP release at the apical surface of human airway epithelia
J. Biol. Chem.
Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis
J. Pediatr.
Pulmonary air cysts in cystic fibrosis: relation of pathologic features to radiologic findings and history of pneumothorax
Hum. Pathol.
Structural airway abnormalities in infants and young children with cystic fibrosis
J. Pediatr.
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.
Tripartite management of unfolded proteins in the endoplasmic reticulum
Cell
Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals
Curr. Opin. Cell Biol.
The ΔF508 mutation disrupts packing of the transmembrane segments of the cystic fibrosis transmembrane conductance regulator
J. Biol. Chem.
A phase I trial of intranasal Moli1901 for cystic fibrosis
Chest
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA
Science
Identification of the cystic fibrosis gene: genetic analysis
Science
Assembly of functional CFTR chloride channels
Annu. Rev. Physiol.
New insights into cystic fibrosis: molecular switches that regulate CFTR
Nat. Rev. Mol. Cell Biol.
Cystic fibrosis since 1938
Am. J. Respir. Crit. Care Med.
CFTR inhibition mimics the cystic fibrosis inflammatory profile
Am. J. Physiol. Lung Cell. Mol. Physiol.
Cytokine secretion by cystic fibrosis airway epithelial cells
Am. J. Respir. Crit. Care Med.
Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections
Science
Ion composition of airway surface liquid of patients with cystic fibrosis as compared to normal and disease-control subjects
J. Clin. Invest.
Desiccation and hypertonicity of the airway surface fluid and thermally induced asthma
J. Appl. Physiol.
Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease
Am. J. Physiol. Cell Physiol.
Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis
Am. J. Physiol. Cell Physiol.
Acinar origin of CFTR-dependent airway submucosal gland fluid secretion
Am J Physiol Lung Cell Mol. Physiol
Submucosal glands and airway defense
Proc. Am. Thorac. Soc.
Cystic fibrosis and airway submucosal glands
Pediatr. Pulmonol.
Cited by (213)
Restoring airway epithelial homeostasis in Cystic Fibrosis
2023, Journal of Cystic FibrosisLessons from other fields of medicine, Part 2: Cystic fibrosis
2023, Handbook of Clinical NeurologyMucus and mucus flake composition and abundance reflect inflammatory and infection status in cystic fibrosis
2022, Journal of Cystic FibrosisMucus-targeting therapies of defective mucus clearance for cystic fibrosis: A short review
2022, Current Opinion in PharmacologySmall-molecule drugs for cystic fibrosis: Where are we now?
2022, Pulmonary Pharmacology and Therapeutics