Cystic fibrosis (CF) is the most common lethal inherited disease among white people. It is an autosomal recessive disease caused by mutations in the CFTR gene. Chronic bacterial lung infection, progressive decline in lung function, and premature death at an average age of 38 years characterize it. More than 1000 mutations of the CFTR gene have been described, but at least one allele in 70% of affected individuals has a deletion of phenylalanine at codon 508 (ΔF508-CFTR). This specific mutation results in a lack of Cl− secretion and an increase in ENaC-mediated Na+ reabsorption, leading to a reduction in the volume of the periciliary fluid.

Detailed study of the various CFTR mutations has provided an understanding of different disease-related phenotypes. Some of these phenotypes are associated with milder disease, while others are associated with more severe disease. Research findings since the 1980s have elucidated how many of the most common mutations in the CFTR gene cause CF. As a result, drugs that target specific mutations have been developed to reverse the reduction in lung function. For example, in one mutation (G551D-CFTR), which affects approximately 5% of CF patients, the CFTR Cl− channel reaches the plasma membrane of airway epithelial cells but does not secrete Cl−. Precision medicine has identified a drug called ivacaftor (Kalydeco) that stimulates Cl− secretion via the G551D-CFTR, thereby improving lung function and slowing the rate of disease progression. However, in cases where the alleles are homozygous for the ΔF508CFTR mutation (which affects approximately 50% of CF patients), the CFTR Cl− channel does not reach the plasma membrane of airway epithelial cells.

In 2015, the U.S. Food and Drug Administration approved a combination drug therapy called lumacaftor/ivacaftor (Orkambi), which has been shown to correct the gene defect, increase the amount of ΔF508-CFTR in the plasma membrane, and improve Cl− transport. Clinically, both ivacaftor and lumacaftor/ivacaftor have been proven to significantly improve lung function and slow the rate of decline in lung function.

Mucus plugging can cause obstruction and reduction in lung function. Four cell types contribute to the quantity and composition of the mucus layer: goblet cells and Clara cells within the tracheobronchial epithelium, and mucous cells and serous cells within the tracheobronchial submucosal glands. Goblet cells, also known as surface secretory cells, make up approximately 15% to 20% of the tracheobronchial epithelium and are present in the tracheobronchial tree up to the 12th division. In various respiratory diseases, goblet cells can extend further down the tracheobronchial tree, making the smaller airways more susceptible to obstruction. Goblet cells secrete neutral and acidic glycoproteins rich in sialic acid in response to chemical stimuli. In the presence of infection, cigarette smoke, or chronic bronchitis, goblet cells can increase in size and number, secrete large amounts of mucus, and extend above the 12th division of the tracheobronchial tree. Injury and infection increase the viscosity of the mucus secreted by goblet cells, which impairs the clearance of inhaled particles and pathogens by the mucociliary system.
Cystic fibrosis (CF)isthemostcommonlethalinheriteddiseaseamongwhitepeople.ItisanautosomalrecessivediseasecausedbymutationsintheCFTR gene.Itischaracterizedbychronicbacteriallunginfection,progressivedeclineinlungfunction,andprematuredeathatanaverageageof38years.Morethan1000mutationsoftheCFTR genehavebeendescribed,but70%ofaffectedindividualshaveadeletionofphenylalanineatcodon508(ΔF508-CFTR)inatleastoneallele.ThismutationresultsinalackofCl− secretionandanincreaseinENaC-mediatedNa+ reabsorption,whichinturnresultsinareductioninthevolumeofthepericiliaryfluid.
DetailedstudyofthedifferentCFTR mutationshasresultedinanunderstandingofvariousdisease-relatedphenotypes,someofwhichareassociatedwithmilderdiseaseandsomewithmoreseveredisease.Sincethe1980s,researchfindingshaveelucidatedhowmanyofthemostcommonmutationsintheCFTR genecauseCF,andthishasledtothedevelopmentofdrugsthattargetspecificmutationsandreversethe individuals produce approximately 100 mL of mucus each day. Four cell types contribute to the quantity and composition of the mucus layer: goblet cells and Clara cells within the tracheobronchial epithelium, and mucous cells and serous cells within the tracheobronchial submucosal glands. Goblet cells, also referred to as surface secretory cells, represent approximately 15% to 20% of the tracheobronchial epithelium, and are found in the tracheobronchial tree up to the 12th division. In many respiratory diseases, goblet cells appear further down the tracheobronchial tree; thus the smaller airways are more susceptible to obstruction progressivereductioninlungfunction.Forexample,inonemutation(G551D-CFTR,whichaffects≈5%ofpatientswithCF),theCFTRCl− channelreachestheplasmamembraneofairwayepithelialcellsbutdoesnotsecreteCl− .Throughprecisionmedicine,adrug,ivacaftor(Kalydeco),hasbeenfoundtostimulateCl− secretionviatheG551D-CFTR,therebyimprovinglungfunctionanddecreasingtherateofdiseaseprogression.WhentheallelesarehomozygousfortheΔF508CFTRmutation(whichaffects≈50%ofpatientswithCF),theCFTRCl− channeldoesnotreachtheplasmamembraneofairwayepithelialcells.
In2015,theU.S.FoodandDrugAdministrationapprovedacombinationdrugtherapy,lumacaftor/ivacaftor(Orkambi),thathasbeenshowntocorrectthegenedefect,increasetheamountofΔF508-CFTRintheplasmamembrane,andimproveCl− transport.Clinically,bothivacaftorandlumacaftor/ivacaftorhavebeenshowntoimprovelungfunctionsignificantlyandtodecreasetherateofdeclineinlungfunction.
by mucus plugging. Goblet cells secrete neutral and acidic glycoproteins rich in sialic acid in response to chemical stimuli. In the presence of infection or cigarette smoke or in patients with chronic bronchitis, goblet cells can increase in size and number, extend above the 12th division of the tracheobronchial tree, and secrete copious amounts of mucus. Injury and infection increase the viscosity of the mucus secreted by goblet cells, which reduces mucociliary clearance of inhaled particles and pathogens.