Boucher, R. C. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu. Rev. Med. 58, 157-170

Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Annual Review of Medicine (Impact Factor: 15.48). 02/2007; 58:157-70. DOI: 10.1146/
Source: PubMed

ABSTRACT Cystic fibrosis (CF) lung disease reflects the failure of airways defense against chronic bacterial infection. Studies of CF cultures, transgenic mice, and CF patients suggest that the initiating event in CF airways disease pathogenesis is reduced airway surface liquid (ASL) volume, i.e., dehydration. CF ASL volume regulation depends on a single extracellular signaling system, ATP, which renders CF airways more vulnerable to disease-causing insults (e.g., viruses) than are normal airways, which regulate ASL volume by dual ATP and adenosine signaling pathways. Clinical studies have explored the hypothesis that treating the dehydration of CF airways will be therapeutically beneficial. Inhaled hypertonic saline osmotically draws water onto airway surfaces, improves mucus clearance and pulmonary function, and reduces acute exacerbations in CF patients. Thus, rehydration therapies may slow the progression of CF lung disease in patients with established bacterial infection and may prevent the onset of CF lung disease if initiated early in life.

  • Source
    • "Although the disease affects a number of organs and systems in the human body, lungs remain the main site of infection in CF patients (Quinton, 1999). The inherited condition stems from the mutation of the CF transmembrane conductance regulator (CFTR) gene, which regulates the transport of chloride ions across the plasma membrane of the epithelial cells (Boucher, 2007). Impaired ion exchange reduces the mucociliary clearance, which leads to accumulation of hyper-viscous mucus in the airway surfaces, thus providing ideal conditions for the growth of microorganisms (Delhaes et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The filamentous fungus Scedosporium aurantiacum and the bacterium Pseudomonas aeruginosa are opportunistic pathogens isolated from lungs of the cystic fibrosis (CF) patients. P. aeruginosa has been known to suppress the growth of a number of CF related fungi such as Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. However, the interactions between P. aeruginosa and S. aurantiacum have not been investigated in depth. Hence we assessed the effect of P. aeruginosa reference strain PAO1 and two clinical isolates PASS1 and PASS2 on the growth of two clinical S. aurantiacum isolates WM 06.482 and WM 08.202 using solid plate assays and liquid cultures, in a synthetic medium mimicking the nutrient condition in the CF sputum. Solid plate assays showed a clear inhibition of growth of both S. aurantiacum strains when cultured with P. aeruginosa strains PASS1 and PAO1. The inhibitory effect was confirmed by confocal microscopy. In addition to using chemical fluorescent stains, strains tagged with yfp (P. aeruginosa PASS1) and mCherry (S. aurantiacum WM 06.482) were created to facilitate detailed microscopic observations on strain interaction. To our knowledge, this is the first study describing successful genetic transformation of S. aurantiacum. Inhibition of growth was observed only in co-cultures of P. aeruginosa and S. aurantiacum; the cell fractions obtained from independent bacterial monocultures failed to initiate a response against the fungus. In the liquid co-cultures, biofilm forming P. aeruginosa strains PASS1 and PAO1 displayed higher inhibition of fungal growth when compared to PASS2. No change was observed in the inhibition pattern when direct cell contact between the bacterial and fungal strains was prevented using a separation membrane suggesting the involvement of extracellular metabolites in the fungal inhibition. However, one of the most commonly described bacterial virulence factors, pyocyanin, had no effect against either of the S. aurantiacum strains. This study shows that P. aeruginosa has a substantial inhibitory effect on the growth of the recently described CF fungal pathogen S. aurantiacum. The findings also highlighted that P. aeruginosa biofilm formation is important but not crucial for inhibiting the growth of S. aurantiacum in a lung- mimicking environment.
    • "The controlled absorption of Na+ from the liquid film covering the lung / airway epithelia is vital to the integrated functioning of the respiratory tract and occurs via a ‘leak-pump′ mechanism in which the overall rate of Na+ absorption is limited by the rate of apical Na+ entry though epithelial Na+ channels (ENaC). Glucocorticoids are clearly important to the induction and maintenance of this Na+ absorbing phenotype and synthetic glucocorticoids are therefore used in the clinical management of conditions, such as respiratory distress and pulmonary oedema, that involve dysfunction of pulmonary Na+ absorption (Barker and Olver, 2002; Boucher, 2004; 2007; Matthay et al., 2002; Olver et al., 2004; Wilson et al., 2007). However, despite their clear importance, the mechanisms that allow these hormones to control pulmonary Na+ transport are not understood fully (Barnes, 2011; Matthay et al., 2002; Olver et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural precursor cell expressed, developmentally down-regulated protein 4-2 (Nedd4-2) mediates the internalization / degradation of epithelial Na+ channel subunits (α-, β- and γ-ENaC). Serum / glucocorticoid inducible kinase 1 (SGK1) and protein kinase A (PKA) both appear to inhibit this process by phosphorylating Nedd4-2-Ser221, -Ser327 and -Thr246. This Nedd4-2 inactivation process is thought to be central to the hormonal control of Na+ absorption. The present study of H441 human airway epithelial cells therefore explores the effects of SGK1 and / or PKA upon the phosphorylation / abundance of endogenous Nedd4-2; the surface expression of ENaC subunits, and electrogenic Na+ transport. Effects on Nedd4-2 phosphorylation / abundance and the surface expression of ENaC were monitored by western analysis, whilst Na+ absorption was quantified electrometrically. Acutely (20 min) activating PKA in glucocorticoid-deprived (24 h) cells increased the abundance of Ser221-phosphorylated, Ser327-phosphorylated and total Nedd4-2 without altering the abundance of Thr246-phosphorylated Nedd4-2. Activating PKA under these conditions did not cause a co-ordinated increase in the surface abundance of α-, β- and γ-ENaC and had only a very small effect upon electrogenic Na+ absorption. Activating PKA (20 min) in glucocorticoid-treated (0.2 µM dexamethasone, 24 h) cells, on the other hand, increased the abundance of Ser221-, Ser327- and Thr246-phosphorylated and total Nedd4-2; increased the surface abundance of α-, β- and γ-ENaC and evoked a clear stimulation of Na+ transport. Chronic glucocorticoid stimulation therefore appears to allow cAMP-dependent control of Na+ absorption by facilitating the effects of PKA upon the Nedd4-2 and ENaC subunits.
    European journal of pharmacology 06/2014; 732(100). DOI:10.1016/j.ejphar.2014.03.005 · 2.68 Impact Factor
  • Source
    • "This impairs muco-ciliary clearance and innate immune defence mechanisms in the airways, favouring chronic bacterial colonization. A cycle of persistent infection and hyper inflammation is set up, eventually manifesting as bronchiectasis and progressive lung destruction [5]. A central difficulty in attempting to ameliorate the basic defect of CFTR dysfunction in CF pertains to regulation of intracellular calcium concentration. "
Show more