Abstract
Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR protein is known to acts as a chloride (Cl−) channel expressed in the exocrine glands of several body systems where it also regulates other ion channels, including the epithelial sodium (Na+) channel (ENaC) that plays a key role in salt absorption. This function is crucial to the osmotic balance of the mucus and its viscosity. However, the pathophysiology of CF is more challenging than a mere dysregulation of epithelial ion transport, mainly resulting in impaired mucociliary clearance (MCC) with consecutive bronchiectasis and in exocrine pancreatic insufficiency. This review shows that the CFTR protein is not just a chloride channel. For a long time, research in CF has focused on abnormal Cl− and Na+ transport. Yet, the CFTR protein also regulates numerous other pathways, such as the transport of HCO3−, glutathione and thiocyanate, immune cells, and the metabolism of lipids. It influences the pH homeostasis of airway surface liquid and thus the MCC as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF.
Highlights
Cystic fibrosis (CF) is the most common life-shortening genetic disease in Caucasian people [1,2,3]
Homeostasis of airway surface liquid and the mucociliary clearance (MCC) as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF
In addition to describing the main known function of the CFTR protein as a Cl− channel, this review focusses on the relationships between the CFTR protein and the transport of HCO3 −, glutathione (GSH), and thiocyanate (SCN− ), as well as the immune cells and the metabolism of lipids that influence MCC and innate immunity and lead to chronic infection and inflammation, all of which are considered as key characteristics in the pathophysiology of CF
Summary
Cystic fibrosis (CF) is the most common life-shortening genetic disease in Caucasian people [1,2,3]. CF is a recessive disease resulting from mutations in a single gene that encodes a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). More than 2000 gene variants have been identified so far. These mutations have different effects on the CFTR protein synthesis, function, and stability at the cell membrane [1]. They have been classified into six or even seven classes [1,6], which are essential for understanding the pathophysiology and developing new therapeutic approaches for CF, such as the CFTR modulators that increase qualitatively and quantitatively the CFTR protein activity.
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