Trends in Molecular Medicine
Volume 8, Issue 11, 1 November 2002, Pages 512-519
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Review
Hyperacidification in cystic fibrosis: links with lung disease and new prospects for treatment

https://doi.org/10.1016/S1471-4914(02)02414-0Get rights and content

Abstract

A new link between the genetic defect and lung pathology in cystic fibrosis (CF) has been established by the recent discovery of an abnormally acidic pH in the organelles of CF respiratory epithelial cells, along with an increased acidity of the CF airway surface liquid. The defect in cystic fibrosis transmembrane resistance regulator (CFTR) results in hyperacidification of the trans-Golgi network, an organelle responsible for glycosylation, and protein- and membrane-sorting in mammalian cells. Hyperacidification and altered surface glycoconjugates might contribute to mucus thickening, bacterial adhesion and colonization, inflammation, and irreversible tissue damage. The increased acidity of the intracellular organelles and of the lung lining in CF could be linked, and both represent potential therapeutic targets.

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

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