Cystic Fibrosis

Abstract

This article has sections titled

1 Introduction
2 The CF Gene
3 The CFTR Protein and Its Function
4 Pathophysiology
5 Mutations in the CFTR Gene
6 Genotype/Phenotype Correlation
7 Presentation
8 Abundance of CF Heterozygotes in Non‐CF Disease Populations
9 Diagnostic Tests
10 Conventional Clinical Management
10.1 Respiratory involvement
10.2 Gastrointestinal treatment
10.3 Management of diabetes mellitus
10.4 Other issues
11 The Development of New CF Therapies
11.1 Gene therapy
11.2 Pharmacological therapy
12 Conclusions

Keywords: cystic fibrosis; lung disease; pseudomonas aeruginose

Figure 1.

Structure of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. (a) The protein has a tandem repeat structure with two identical halves, each consisting of six putative transmembrane α‐helices and an intracellular nucleotide‐binding domain (NBD1+2). NBD1+2 binds to ATP and hydrolyses it to adenosine diphosphate (ADP) and inorganic phosphate (Pi). The two halves of the protein are linked through a highly charged intracellular regulatory domain (R domain), which contains numerous phosphorylation sites. (b) These sites are phosphorylated by c‐AMP‐dependent PKA. This process leads to conformational changes in the protein and channel opening. (c) CFTR expression in the apical membrane of human airway epithelial cells. CFTR is visualized as a red signal in a primary human airway epithelial cell after staining with a fluorescently labelled antihuman CFTR antibody (arrow). The cell nucleus is shown blue. Adapted from Dr Marguerite Wasowicz, Department of Gene Therapy, Imperial College London.

Figure 2.

CFTR regulates a number of other channels in the apical membrane of epithelial cells. The ENaC is inhibited by CFTR and alternative chloride channels (Ca alternative), such as the calcium‐activated chloride channel are activated by CFTR.

Figure 3.

Decreased airway surface liquid in CF airways. ASL covers the apical membrane of airway epithelial cells. ASL height is tightly regulated with an adequate height important for efficient mucociliary clearance. In CF, increased sodium (Na+) absorption leads to increased water absorption and reduced ASL. Mucociliary clearance is, therefore, decreased and leads to mucus accumulation in the airways. Schematic diagram of ASL in CF and non‐CF airways. By courtesy of Professor Boucher R, University of North Carolina at Chapel Hill.

Figure 4.

Adolescent with classical radiological appearances of CF, severe widespread bronchiectasis (left hand side), consolidation of the right middle lobe (obscuring the right heart border, thick arrow) and a right‐sided pneumothorax (thin arrow). Histology image of a normal and a CF lung (original magnification 10×).

Figure 5.

Abdominal and chest radiographs of an infant ventilated shortly after birth with a tense, distended abdomen and absent bowel sounds. Dilated bowel loops are visible, and the free intraperitoneal air demonstrates a perforated bowel. This infant had meconium ileus and was subsequently diagnosed with CF.

Figure 6.

CFTR‐related disease. There a number of diseases in which the frequency of CFTR mutations is higher than in the general population. COPD, chronic obstructive pulmonary disease; ABPA, allergic bronchopulmonary aspergillosis; CBAVD, congenital bilateral absence of the vas deferens; PS, pancreatic sufficiency; PI, pancreatic insufficiency.

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Further Reading

Donaldson SH and Boucher RC (2003) Update on pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine 9(6): 486–491.

Gibson RL, Burns JL and Ramsey BW (2003) Pathophysiology and management of pulmonary infections in cystic fibrosis. American Journal of Respiratory Critical Care Medicine 168(8): 918–951.

Griesenbach U, Geddes DM and Alton EWFW (2004) Gene therapy for cystic fibrosis: an example for lung gene therapy. Gene Therapy 11 (suppl. 1): S43–S50.

Lim M and Zeitlin PL (2001) Therapeutic strategies to correct malfunction of CFTR. Paediatric Respiratory Review 2: 159–164.

Online Mendelian Inheritance in Mean: Cystic Fibrosis http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=219700.

Schildow DV and Friel SB (2004) In: Albert RK, Spiro SG and Jett JR (eds) Cystic Fibrosis in Clinical Respiratory Medicine. USA: Mosby.

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How to Cite close
Davies, Jane C, Griesenbach, Uta, Geddes, Duncan M, and Alton, Eric WFW(Jan 2006) Cystic Fibrosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0002005]