Since its cloning in 1989, tremendous work has gone into understanding how the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) contributes to normal and disease physiology in epithelial tissues.
CFTR functions as a chloride and bicarbonate channel in epithelial cells. By regulating the secretion of these two anions, as well as regulating the functions of muliple associated ion channels, CFTR serves to hydrate and buffer fluid secretions across epithelial tissues. The loss of functional CFTR at the cell surface of these tissues causes CF. The most common mutations found in the CF patient popultation lead to a loss of protein function at the cell surface, resutling from altered biosynthesis or loss of protein activity.
Under normal conditions, fluid secretion is buffered and regulated by epithelial ion channels, including CFTR and ENaC, left. This hydration facilitates muco-cilliary clearance of the airway and protects against viral, fungal and bacterial infection. In CF, the loss of the CFTR channel results in altered chloride and bicarbonate secretion and dehydration of the airway surface liquid, center. This inihibits the muco-cilliary cleareance of pathogens and leads to their adherance within the airway and colonization, right. The persistant immune and inflammatory response, resulting from this chronic infection, leads to damage to the epithelial tissue and contributes to the loss of lung function.
Changes in fluid and bicarboante secretion by CFTR in the pancreas are responsible for pancreatic insufficiency in CF. A primary function of the pancreas is the secretion of digestive enzymes into the stomach via the pancreatic duct. These enzymes are regulated, in part, by fluid pH. The dysregulated buffering of fluid pH in the pancreatic duct, resulting from the loss of CFTR bicarboante secretion, causes premature activation of pancreatic enzymes and induces damage to the pancreas.