Cystic fibrosis, a recessive autosomal disease, is characterized by chronic lung infections, pancreatic insufficiency, and infertility in boys and men. Death is typically caused by respiratory failure. This genetic disease is most prevalent in white people and is the most common lethal genetic disorder among this population, occurring in 1 out of every 3000 live births. It is caused by mutations in a gene on chromosome 7 that codes for an ABC transporter. Over 1000 mutations in this gene have been identified to date. The most common mutation is a deletion of a phenylalanine at position 508 (F508del). This deletion enhances protein degradation by the endoplasmic reticulum, preventing the transporter from reaching the plasma membrane. The cystic fibrosis transmembrane conductance regulator (CFTR), which normally functions as a Cl− channel and regulates other membrane transporters such as the epithelial Na+ channel (ENaC), is affected in individuals with cystic fibrosis. As a result, epithelial transport is defective, leading to the pathophysiological processes associated with the disease. In unaffected individuals, the airway epithelial cells are covered with a layer of mucus that traps inhaled particulates and bacteria. Cilia on these cells transport the trapped material out of the lungs, a process known as mucociliary transport. In patients with cystic fibrosis, the inability to secrete Cl−, Na+, and H2O leads to an increase in the viscosity of the airway surface mucus. As a result, cilia are unable to transport the trapped bacteria and pathogens out of the lungs, resulting in recurrent and chronic lung infections. The inflammatory process accompanying these infections eventually leads to the destruction of lung tissue, causing respiratory failure and death. In 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor (Orkambi), a drug that increases the amount of F508delCFTR in the plasma membrane of lung epithelial cells.

Endocytosis and exocytosis are cellular processes that involve the internalization and release of substances through the plasma membrane. Endocytosis occurs in three mechanisms. The first is pinocytosis, which involves the nonspecific uptake of small molecules and water into the cell. Endothelial cells lining capillaries exhibit pinocytosis and contribute to fluid exchange across these vessels. The second form of endocytosis is phagocytosis, which allows for the cellular internalization of large particles such as bacteria and cell debris. This process is particularly important in immune system cells like neutrophils and macrophages. Phagocytosis can be receptor-mediated, but not always. In certain cases, endocytosis across one membrane is followed by exocytosis across the opposite membrane, enabling the transport of substances within vesicles across the epithelium. This process is known as transcytosis.

Chapter 1: Principles of Cell and Membrane Function
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