Cystic fibrosis isanautosomalrecessivediseasecharacterizedbychroniclunginfections,pancreaticinsufficiency,andinfertilityinboysandmen.Deathusuallyoccursbecauseofrespiratoryfailure.Itismostprevalentinwhitepeopleandisthemostcommonlethalgeneticdiseaseinthispopulation,occurringin1per3000livebirths.Itisaresultofmutationsinageneonchromosome7thatcodesforanABCtransporter.Todate,morethan1000mutationsinthegenehavebeenidentified.Themostcommonmutationisadeletionofaphenylalanineatposition508(F508del).Becauseofthisdeletion,degradationoftheproteinbytheendoplasmicreticuluminenhanced,and,asaresult,thetransporterdoesnotreachtheplasmamembrane.Thistransporter,calledcystic fibrosis transmembrane conductance regulator (CFTR), normallyfunctionsasaCl− channelandalsoregulatesothermembranetransporters(e.g.,theepithelialNa+ channel[ENaC]).Thusinindividualswithcysticfibrosis,epithelialtransportisdefective,whichisresponsibleforthepathophysiologicprocess.Forexample,inpatientsnotaffectedbycysticfibrosis,theepithelialcellsthatlinetheairwayofthelungarecoveredwithalayerofmucusthatentrapsinhaledparticulatesandbacteria.Ciliaontheepithelialcellsthentransporttheentrappedmaterialoutofthelung,aprocesstermedmucociliary transport (see formoredetails).Inpatientswithcysticfibrosis,theinabilitytosecreteCl− ,Na+ ,andH2Oresultsinanincreaseintheviscosityoftheairwaysurfacemucus;thustheciliacannottransporttheentrappedbacteriaandotherpathogensoutofthelung.Thisinturnleadstorecurrentandchroniclunginfections.Theinflammatoryprocessthataccompaniestheseinfectionsultimatelydestroysthelungtissue,causingrespiratoryfailureanddeath.In2015,the
U.S.FoodandDrugAdministrationapprovedlumacaftor/ivacaftor(Orkambi),adrugthatincreasestheamountofF508delCFTRintheplasmamembraneoflungepithelialcells.
is internalized into the cell interior, and exocytosis is the process whereby vesicles inside the cell fuse with the plasma membrane. In both of these processes, the integrity of the plasma membrane is maintained, and the vesicles allow for the transfer of the contents among cellular compartments. In some cells (e.g., the epithelial cells lining the gastrointestinal tract), endocytosis across one membrane of the cell is followed by exocytosis across the opposite membrane. This allows the transport of substances inside the vesicles across the epithelium, a process termed transcytosis.
Endocytosis occurs in three mechanisms. The first is pinocytosis, which consists of the nonspecific uptake of small molecules and water into the cell. Pinocytosis is a prominent feature of the endothelial cells that line capillaries and is responsible for a portion of the fluid exchange that occurs across these vessels. The second form of endocytosis, phagocytosis, allows for the cellular internalization of large particles (e.g., bacteria, cell debris). This process is an important characteristic of cells in the immune system (e.g., neutrophils and macrophages). Often, but not always, phagocytosis is a receptor-mediated process. For example,
CHAPTER 1 Principles of Cell and Membrane Function 9