Cystic fibrosis is an inherited disease caused by mutations in the CFTR gene. Each mutation has number of effects on lung cells. New in vitro evidence published in the Journal of Clinical Investigation has provided insight into the mechanisms by which one of these changes impacts both CF and the complications of CF, providing support for ongoing clinical trials and raising the possibility of new targets for the development of drugs to treat CF.
CFTR mutations that cause CF make a compartment of the cell known as the TGN more acidic than it is in cells from healthy individuals. In this study, in vitro analysis revealed that hyperacidification of the TGN causes increased activity of a protein known as furin. Through increased production of a soluble factor known as TGF-beta this augmented the production of collagen (which in situ is associated with tissue fibrosis, a characteristic of damaged lung in individuals with CF) and suppressed the ability of human macrophages to kill the bacterium Pseudomonas aeruginosa, infection with which is a major complication for individuals with CF. This study provides strong support for the use of chloroquine (which counteracts high levels of TGN acidity) to treat CF, something that is currently being tested in clinical trials, and identifies furin inhibitors as potential new therapeutics for the treatment of CF.