Trends in Molecular Medicine
ReviewHyperacidification in cystic fibrosis: links with lung disease and new prospects for treatment
Section snippets
Genetic and physiological basis of CF
CF is caused by mutations in the gene CFTR (cystic fibrosis transmembrane conductance regulator) (Fig. 1) [3]. The disease is inherited as a simple recessive trait. Recently, it has been postulated that additional, modifier genes might affect the severity of CF 4., 5.. Although a great deal is known about the function of CFTR in electrolyte transport, there is currently no consensus on how the malfunction in CFTR leads to fatal respiratory infections. CFTR functions primarily as a
Respiratory infections and inflammation in CF
It is widely acknowledged that progressive deterioration of respiratory function in CF is the result of recurring bacterial infections and persistent colonization with a characteristic subset of bacterial pathogens (Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia, and non-tuberculous mycobacteria) [2]. P. aeruginosa is particularly difficult to treat because it develops resistance to antibiotic therapy, and cannot be eradicated from the CF lung.
CFTR and CF pathophysiology: a wide range of hypotheses
Over the years, many hypotheses that attempt to link the CFTR defect with lung pathogenesis have been put forward. Described below are some of the more prominent explanations for the respiratory problems associated with CF.
The defective glycosylation hypothesis
It has long been known that glycoproteins and glycolipids on the plasma membranes of CF cells display altered sialylation, and possess other, more complex glycosylation anomalies. The types of aberration differ for cell-associated glycoconjugates or secreted mucins [33]. For example, it has been shown [33] that, in CF, plasma-membrane-associated glycoproteins have a decreased sialic-acid content and an increase in fucosyl modifications (α1,6-linked fucose to the N-proximal core N
Abnormal hyperacidification of the trans-Golgi network in CF cells
Expression of ΔF508 CFTR in transfected cells results in decreased sialylation of glycoconjugates on the plasma membrane [37]. Similarly, expression of a dominant-negative R domain of CFTR reduces sialylation of glycolipids and increases P. aeruginosa adherence to epithelial cells [49]. To explain these results, it has been proposed that sialyltransferases in the TGN, a major intracellular biosynthetic organelle where final glycosylations are applied to glycoconjugates destined for the plasma
Hyperacidification of intracellular organelles and airway surface liquid in CF
The reduced pH of the lumen of biosynthetic organelles in CF cells that we reported 14., 15. has been independently confirmed by others [53]. Hyperacidification has also been detected in the recycling endosome of CF lung epithelial cells [15], in the lung lining fluid 54., 55., and in exhaled breath condensate 56., 57.. However, it remains to be determined whether there is a direct connection between increased endosomal and ASL acidity. The consequences of hyperacidified ASL in CF lungs are not
Prospects for new pH-balancing therapies in CF
Uncovering the connections between the CFTR defect and lung pathogenesis is a prerequisite for effective management of respiratory problems in CF. A model of the downstream consequences of organellar hyperacidification in CF is given in Fig. 4, although this is likely to be revised as new information becomes available. The finding that the major biosynthetic organelle, the TGN, and also the endosomal compartments and the ASL, are hyperacidic in CF, and that this is connected with disease
Acknowledgements
We thank Rebecca Van Dyke for past discussions, and Cliff Boucher, Aaron Firoved and Lisa Tatterson for experimental contributions to the findings discussed in this review. This work was supported by grants AI31139 and AI50825 from the National Institutes of Health, and a grant from the Philip Morris External Research Program to V.D. E.P was supported by a CF center grant from the Cystic Fibrosis Foundation and 6 T72 MC 00004–11 grant from the Maternal Child Health Bureau. J.P. was a Cystic
References (61)
Hyperacidification of cellubrevin endocytic compartments and defective endosomal recycling in cystic fibrosis respiratory epithelial cells
J. Biol. Chem.
(2002)Human β-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis
Cell
(1997)Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid
Cell
(1996)Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease
Cell
(1998)Cystic fibrosis and the salt controversy. Cell
(1999)- et al.
Terminal glycosylation in cystic fibrosis
Biochim. Biophys. Acta
(1999) Additional fucosyl residues on membrane glycoproteins but not a secreted glycoprotein from cystic fibrosis fibroblasts
Clin. Chim. Acta
(1990)Cystic fibrosis pathogens activate Ca2+-dependent mitogen-activated protein kinase signaling pathways in airway epithelial cells
J. Biol. Chem.
(2001)Evidence against defective trans-Golgi acidification in cystic fibrosis
J. Biol. Chem.
(1996)Cystic fibrosis in adolescents and young adults
Adolesc. Med.
(2000)
Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia
Microbiol. Rev.
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA
Science
TGF-β1 genotype and accelerated decline in lung function of patients with cystic fibrosis
Thorax
HLA class II polymorphism in cystic fibrosis. A possible modifier of pulmonary phenotype
Am. J. Respir. Crit. Care Med.
CFTR is a conductance regulator as well as a chloride channel
Physiol. Rev.
Biosynthesis and degradation of CFTR
Physiol. Rev.
CFTR as a cAMP-dependent regulator of sodium channels
Science
The first nucleotide binding domain of the cystic-fibrosis transmembrane conductance regulator is important for inhibition of the epithelial Na+ channel
Proc. Natl. Acad. Sci. U. S. A.
Aberrant CFTR-dependent HCO3− transport in mutations associated with cystic fibrosis
Nature
Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms
Nature
Effect of high-dose ibuprofen in patients with cystic fibrosis
N. Engl. J. Med.
Inflammatory cytokines in cystic fibrosis lungs
Am. J. Respir. Crit. Care Med.
Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung
Proc. Natl. Acad. Sci. U. S. A.
Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects
J. Clin. Invest.
Airway surface liquid osmolality measured using fluorophore-encapsulated liposomes
J. Gen. Physiol.
Submucosal gland secretions in airways from cystic fibrosis patients have normal [Na+] and pH but elevated viscosity
Proc. Natl. Acad. Sci. U. S. A.
Mucociliary transport in trachea of patients with cystic fibrosis
Arch. Dis. Child.
Systemic deficiency of glutathione in cystic fibrosis
J. Appl. Physiol.
Role of the cystic fibrosis transmembrane conductance regulator in innate immunity to Pseudomonas aeruginosa infections
Proc. Natl. Acad. Sci. U. S. A.
Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections
Science
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