Editing Cystic fibrosis (section)

==Pathophysiology==
[[File:CFTR Protein Panels.svg|thumb|upright=1.3|The CFTR protein is a channel protein that controls the flow of H<sub>2</sub>O and Cl<sup>−</sup> ions in and out of cells inside the lungs. When the CFTR protein is working correctly, ions freely flow in and out of the cells. However, when the CFTR protein is malfunctioning, these ions cannot flow out of the cell due to a blocked channel. This causes cystic fibrosis, characterized by the buildup of thick mucus in the lungs.]]
The ''CFTR'' gene regulates the transport of salts and water through cell membranes, providing instructions for creating a pathway that allows the passage of chloride ions.<ref name="pmid9922379">{{cite journal | vauthors = Schwiebert EM, Benos DJ, Egan ME, Stutts MJ, Guggino WB | title = CFTR is a conductance regulator as well as a chloride channel | journal = Physiological Reviews | volume = 79 | issue = 1 Suppl | pages = S145–S166 | date = January 1999 | pmid = 9922379 | doi = 10.1152/physrev.1999.79.1.S145 }}</ref> A mutation in the CFTR gene can impair the normal function of chloride channels, leading to abnormal transport of chloride ions and water, resulting in the formation of thick and abnormal mucus.<ref name="pmid16157656">{{cite journal | vauthors = Linsdell P | title = Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel | journal = Experimental Physiology | volume = 91 | issue = 1 | pages = 123–129 | date = January 2006 | pmid = 16157656 | doi = 10.1113/expphysiol.2005.031757 | s2cid = 37254079 }}</ref>

In the pancreatic duct chloride transport occurs through the voltage-gated chloride channels influenced by CFTR (Cystic Fibrosis transmembrane conductance regulator). These channels are localised in the apical membrane of epithelial cells in the pancreatic duct.<ref name="Pal-2023">{{Cite book | vauthors = Pal GK |title=Comprehensive Textbook of Medical Physiology , Medical |publisher=Jaypee Brothers Medical Publishers |year=2023 |isbn=9789356962897 |edition=3rd |location= Daryaganj, New Delhi, India |publication-date=July 2023 |pages=643–44 |language=}}</ref>

Several mutations in the ''CFTR'' gene can occur, and different mutations cause different defects in the CFTR protein, sometimes causing a milder or more severe disease. These protein defects are also targets for drugs which can sometimes restore their function. [[ΔF508|ΔF508-CFTR]] gene mutation, which occurs in >90% of patients in the U.S., creates a protein that does not [[Protein folding|fold]] normally and is not appropriately transported to the cell membrane, resulting in its degradation.<ref name="pmid24970227">{{cite journal | vauthors = Wang XR, Li C | title = Decoding F508del misfolding in cystic fibrosis | journal = Biomolecules | volume = 4 | issue = 2 | pages = 498–509 | date = May 2014 | pmid = 24970227 | pmc = 4101494 | doi = 10.3390/biom4020498 | doi-access = free }}</ref>

Other mutations result in proteins that are too short (truncated) because [[Translation (genetics)|production]] is ended prematurely. Other mutations produce proteins that do not use energy (in the form of ATP) normally, do not allow chloride, iodide, and thiocyanate to cross the membrane appropriately,<ref name="pmid16934416">{{cite journal | vauthors = Childers M, Eckel G, Himmel A, Caldwell J | title = A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates | journal = Medical Hypotheses | volume = 68 | issue = 1 | pages = 101–112 | date = 2007 | pmid = 16934416 | doi = 10.1016/j.mehy.2006.06.020 }}</ref> and degrade faster than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.<ref name="Rowe" />

The protein created by this gene is anchored to the [[cell membrane|outer membrane]] of cells in the [[sweat gland]]s, lungs, pancreas, and all other remaining exocrine glands in the body.
The protein spans this membrane and acts as a [[Ion channel|channel]] connecting the inner part of the cell ([[cytoplasm]]) to the [[extracellular fluid|surrounding fluid]]. This channel is primarily responsible for controlling the movement of halide anions from inside to outside of the cell; however, in the sweat ducts, it facilitates the movement of chloride from the sweat duct into the cytoplasm. When the CFTR protein does not resorb ions in sweat ducts, chloride, and thiocyanate<ref name="pmid19918082">{{cite journal | vauthors = Xu Y, Szép S, Lu Z | title = The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 48 | pages = 20515–20519 | date = December 2009 | pmid = 19918082 | pmc = 2777967 | doi = 10.1073/pnas.0911412106 | doi-access = free | bibcode = 2009PNAS..10620515X }}</ref> released from sweat glands are trapped inside the ducts and pumped to the skin.

Additionally [[hypothiocyanite]], OSCN, cannot be produced by the immune defense system.<ref name="pmid17082494">{{cite journal | vauthors = Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B | title = A novel host defense system of airways is defective in cystic fibrosis | journal = American Journal of Respiratory and Critical Care Medicine | volume = 175 | issue = 2 | pages = 174–183 | date = January 2007 | pmid = 17082494 | pmc = 2720149 | doi = 10.1164/rccm.200607-1029OC }}</ref><ref name="pmid17204267">{{cite journal | vauthors = Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M | title = The lactoperoxidase system links anion transport to host defense in cystic fibrosis | journal = FEBS Letters | volume = 581 | issue = 2 | pages = 271–278 | date = January 2007 | pmid = 17204267 | pmc = 1851694 | doi = 10.1016/j.febslet.2006.12.025 | bibcode = 2007FEBSL.581..271C }}</ref> Because chloride is [[Electric charge|negatively charged]], this modifies the electrical potential inside and outside the cell that normally causes [[cation]]s to cross into the cell. Sodium is the most common cation in the extracellular space. The excess chloride within sweat ducts prevents sodium resorption by epithelial sodium channels and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.<ref name="Rowe">{{cite journal | vauthors = Rowe SM, Miller S, Sorscher EJ | title = Cystic fibrosis | journal = The New England Journal of Medicine | volume = 352 | issue = 19 | pages = 1992–2001 | date = May 2005 | pmid = 15888700 | doi = 10.1056/NEJMra043184 }}</ref>

Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick feces, etc. Several theories have been posited on how the defects in the protein and cellular function cause the clinical effects. The current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus.<ref name="pmid26719229">{{cite journal | vauthors = Haq IJ, Gray MA, Garnett JP, Ward C, Brodlie M | title = Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets | journal = Thorax | volume = 71 | issue = 3 | pages = 284–287 | date = March 2016 | pmid = 26719229 | doi = 10.1136/thoraxjnl-2015-207588 | doi-access = free }}</ref> In airway epithelial cells, the cilia exist in between the cell's apical surface and mucus in a layer known as airway surface liquid (ASL). The flow of ions from the cell and into this layer is determined by ion channels such as CFTR. CFTR allows chloride ions to be drawn from the cell and into the ASL, but it also regulates another channel called ENac, which allows sodium ions to leave the ASL and enter the respiratory epithelium. CFTR normally inhibits this channel, but if the CFTR is defective, then sodium flows freely from the ASL and into the cell.{{citation needed|date=July 2022}}

As water follows sodium, the depth of ASL will be depleted and the cilia will be left in the mucous layer.<ref name="pmid12475759">{{cite journal | vauthors = Verkman AS, Song Y, Thiagarajah JR | title = Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease | journal = American Journal of Physiology. Cell Physiology | volume = 284 | issue = 1 | pages = C2-15 | date = January 2003 | pmid = 12475759 | doi = 10.1152/ajpcell.00417.2002 | s2cid = 11790119 }}</ref> As cilia cannot effectively move in a thick, viscous environment, mucociliary clearance is deficient and a buildup of mucus occurs, clogging small airways.<ref name="Marieb-2014">{{cite book|title=Human Anatomy and Physiology|vauthors=Marieb EN, Hoehn K, Hutchinson M|publisher=Pearson Education|year=2014|isbn=978-0805361179|pages=906|chapter=22: The Respiratory System}}</ref> The accumulation of more viscous, nutrient-rich mucus in the lungs allows bacteria to hide from the body's immune system, causing repeated respiratory infections. The presence of the same CFTR proteins in the pancreatic duct and sweat glands in the skin also causes symptoms in these systems.{{citation needed|date=July 2022}}

===Chronic infections===
The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as [[biofilm]]s that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lungs by gradually remodeling the airways, which makes infection even more difficult to eradicate.<ref name="Saiman">{{cite journal | vauthors = Saiman L | title = Microbiology of early CF lung disease | journal = Paediatric Respiratory Reviews | volume = 5 | issue = Suppl A | pages = S367–S369 | year = 2004 | pmid = 14980298 | doi = 10.1016/S1526-0542(04)90065-6 }}</ref> The natural history of CF lung infections and airway remodeling is poorly understood, largely due to the immense spatial and temporal heterogeneity both within and between the microbiomes of CF patients.<ref name="Khanolkar">{{cite journal | vauthors = Khanolkar RA, Clark ST, Wang PW, Hwang DM, Yau YC, Waters VJ, Guttman DS | title = Ecological Succession of Polymicrobial Communities in the Cystic Fibrosis Airways | journal = mSystems | volume = 5 | issue = 6 | pages = e00809-20 | date = December 2020 | pmid = 33262240 | pmc = 7716390 | doi = 10.1128/mSystems.00809-20 }}</ref>

Over time, the types of bacteria and their characteristics change in individuals with CF. In the initial stage, common bacteria such as ''S.&nbsp;aureus'' and ''H.&nbsp;influenzae'' colonize and infect the lungs.<ref name=kumar2007/> Eventually, ''[[Pseudomonas aeruginosa]]'' (and sometimes ''[[Burkholderia cepacia complex|Burkholderia cepacia]]'') dominates. By 18 years of age, 80% of patients with classic CF harbor ''P.&nbsp;aeruginosa'', and 3.5% harbor ''B.&nbsp;cepacia''.<ref name=kumar2007/> Once within the lungs, these bacteria adapt to the environment and develop [[antibiotic resistance|resistance]] to commonly used antibiotics. ''Pseudomonas'' can develop special characteristics that allow the formation of large colonies, known as "mucoid" ''Pseudomonas'', which are rarely seen in people who do not have CF.<ref name="Saiman" /> Scientific evidence suggests the [[interleukin 17]] pathway plays a key role in resistance and modulation of the inflammatory response during ''P.&nbsp;aeruginosa'' infection in CF.<ref name="Lorè">{{cite journal | vauthors = Lorè NI, Cigana C, Riva C, De Fino I, Nonis A, Spagnuolo L, Sipione B, Cariani L, Girelli D, Rossi G, Basso V, Colombo C, Mondino A, Bragonzi A | title = IL-17A impairs host tolerance during airway chronic infection by Pseudomonas aeruginosa | journal = Scientific Reports | volume = 6 | pages = 25937 | date = May 2016 | pmid = 27189736 | pmc = 4870500 | doi = 10.1038/srep25937 | bibcode = 2016NatSR...625937L }}</ref> In particular, interleukin 17-mediated immunity plays a double-edged activity during chronic airways infection; on one side, it contributes to the control of ''P.&nbsp;aeruginosa'' burden, while on the other, it propagates exacerbated pulmonary neutrophilia and tissue remodeling.<ref name="Lorè" />

Infection can spread by passing between different individuals with CF.<ref name="pmid1907611">{{cite journal | vauthors = Tümmler B, Koopmann U, Grothues D, Weissbrodt H, Steinkamp G, von der Hardt H | title = Nosocomial acquisition of Pseudomonas aeruginosa by cystic fibrosis patients | journal = Journal of Clinical Microbiology | volume = 29 | issue = 6 | pages = 1265–1267 | date = June 1991 | pmid = 1907611 | pmc = 271975 | doi = 10.1002/pola.1991.080290905 | bibcode = 1991JPoSA..29.1265A }}</ref> In the past, people with CF often participated in summer "CF camps" and other recreational gatherings.<ref name="pmid7684813">{{cite journal | title = Pseudomonas cepacia at summer camps for persons with cystic fibrosis | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 42 | issue = 23 | pages = 456–459 | date = June 1993 | pmid = 7684813 | author-link = Centers for Disease Control and Prevention | author1 = Centers for Disease Control and Prevention (CDC) }}</ref><ref name="pmid7513755">{{cite journal | vauthors = Pegues DA, Carson LA, Tablan OC, FitzSimmons SC, Roman SB, Miller JM, Jarvis WR | title = Acquisition of Pseudomonas cepacia at summer camps for patients with cystic fibrosis. Summer Camp Study Group | journal = The Journal of Pediatrics | volume = 124 | issue = 5 Pt 1 | pages = 694–702 | date = May 1994 | pmid = 7513755 | doi = 10.1016/S0022-3476(05)81357-5 | url = https://zenodo.org/record/1259645 }}</ref> Hospitals grouped patients with CF into common areas and routine equipment (such as [[nebulizer]]s)<ref name="pmid8744509">{{cite journal | vauthors = Pankhurst CL, Philpott-Howard J | title = The environmental risk factors associated with medical and dental equipment in the transmission of Burkholderia (Pseudomonas) cepacia in cystic fibrosis patients | journal = The Journal of Hospital Infection | volume = 32 | issue = 4 | pages = 249–255 | date = April 1996 | pmid = 8744509 | doi = 10.1016/S0195-6701(96)90035-3 }}</ref> was not sterilized between individual patients.<ref name="pmid12775867">{{cite journal | vauthors = Jones AM, Govan JR, Doherty CJ, Dodd ME, Isalska BJ, Stanbridge TN, Webb AK | title = Identification of airborne dissemination of epidemic multiresistant strains of Pseudomonas aeruginosa at a CF centre during a cross infection outbreak | journal = Thorax | volume = 58 | issue = 6 | pages = 525–527 | date = June 2003 | pmid = 12775867 | pmc = 1746694 | doi = 10.1136/thorax.58.6.525 }}</ref> This led to the transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are now routinely isolated from one another in the healthcare setting, and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF to limit the spread of virulent bacterial strains.<ref name="pmid7643943">{{cite journal | vauthors = Høiby N | title = Isolation and treatment of cystic fibrosis patients with lung infections caused by Pseudomonas (Burkholderia) cepacia and multiresistant Pseudomonas aeruginosa | journal = The Netherlands Journal of Medicine | volume = 46 | issue = 6 | pages = 280–287 | date = June 1995 | pmid = 7643943 | doi = 10.1016/0300-2977(95)00020-N }}</ref>

CF patients may also have their airways chronically colonized by filamentous fungi (such as ''Aspergillus fumigatus'', ''[[Scedosporium apiospermum]]'', ''[[Aspergillus terreus]]'') and/or yeasts (such as ''[[Candida albicans]]''); other filamentous fungi less commonly isolated include ''[[Aspergillus flavus]]'' and ''[[Aspergillus nidulans]]'' (occur transiently in CF respiratory secretions) and ''[[Exophiala dermatitidis]]'' and ''[[Scedosporium prolificans]]'' (chronic airway-colonizers); some filamentous fungi such as ''Penicillium emersonii'' and ''[[Acrophialophora fusispora]]'' are encountered in patients almost exclusively in the context of CF.<ref name="Pihet">{{cite journal | vauthors = Pihet M, Carrere J, Cimon B, Chabasse D, Delhaes L, Symoens F, Bouchara JP | title = Occurrence and relevance of filamentous fungi in respiratory secretions of patients with cystic fibrosis--a review | journal = Medical Mycology | volume = 47 | issue = 4 | pages = 387–397 | date = June 2009 | pmid = 19107638 | doi = 10.1080/13693780802609604 | hdl-access = free | doi-access = free | hdl = 20.500.12210/37415 }}</ref> Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, prolonged therapy with antibiotics and corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response and therefore to the progressive deterioration of the lung function, as often happens with allergic bronchopulmonary aspergillosis''&nbsp;''– the most common fungal disease in the context of CF, involving a Th2-driven immune response to ''Aspergillus'' species.<ref name="Pihet" /><ref name="pmid18668399">{{cite journal | vauthors = Rapaka RR, Kolls JK | title = Pathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis: current understanding and future directions | journal = Medical Mycology | volume = 47 | issue = Suppl 1 | pages = S331–S337 | date = 2009 | pmid = 18668399 | doi = 10.1080/13693780802266777 | doi-access = free }}</ref>