The Lancet. Respiratory medicine
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Cystic fibrosis is caused by dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial chloride channel that has a key role in maintaining homoeostasis of the airway surface liquid layer in the lungs. More than 1900 CFTR mutations that might result in a disease phenotype have been identified; these can be grouped into classes on the basis of their effect on CFTR protein production, trafficking, function, and stability. ⋯ These findings are ushering in a new era of cystic fibrosis treatments designed to correct the underlying CFTR defect caused by different mutation classes. With analysis of continuing trials and available patient registries, here we assess mutation types and the number and geographical distribution of patients who are likely to benefit from CFTR-correcting treatment.
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Among patients with cystic fibrosis there is a high prevalence (40-70%) of asthma signs and symptoms such as cough and wheezing and airway hyper-responsiveness to inhaled histamine or methacholine. Whether these abnormal airway responses are due to a primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) or are secondary to the inflammatory environment in the cystic fibrosis lungs is not clear. A role for the CFTR in smooth muscle function is emerging, and alterations in contractile signalling have been reported in CFTR-deficient airway smooth muscle. ⋯ Increased neutrophilia and skewing of CFTR-deficient T-helper cells to type 2 helper T cells creates an inflammatory environment characterised by high concentrations of tumour necrosis factor α, interleukin-8, and interleukin-13, which might all contribute to increased contractility of airway smooth muscle in cystic fibrosis. An emerging role of interleukin-17, which is raised in patients with cystic fibrosis, in airway smooth muscle proliferation and hyper-responsiveness is apparent. Increased understanding of the molecular mechanisms responsible for the altered smooth muscle physiology in patients with cystic fibrosis might provide insight into airway dysfunction in this disease.