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Event: 1906

Key Event Title

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Cystic Fibrosis Transmembrane Regulator Function, Decreased

Short name

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CFTR Function, Decreased

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
epithelial cell

Organ term

Organ term
lung

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
chloride channel activity		decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Ox stress-mediated CFTR/ASL/CBF/MCC impairment	KeyEvent	Karsta Luettich (send email)	Open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Mus musculus	Mus musculus	Moderate	NCBI

Life Stages

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Life stage	Evidence
All life stages	High

Sex Applicability

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Term	Evidence
Mixed	High

Key Event Description

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The cystic fibrosis transmembrane regulator (CFTR) is a multi-domain membrane protein that belongs to the large family of adenine nucleotide binding cassette transporters consisting of two transmembrane domains, two nucleotide binding domains (NBDs) and a unique regulatory domain (Riordan, 2008). It is an integral membrane glycoprotein that functions as cAMP-activated and phosphorylation-regulated Cl^– channel at the apical membrane of epithelial cells (Farinha et al., 2013). In respiratory epithelia, CFTR is the major Cl^– channel that mediates fluid and electrolyte transport, and CFTR function is critical to normal ASL homeostasis. Exposure to inhaled oxidants, such as ozone and cigarette smoke, leads to decreased CFTR gene and protein expression as well as CFTR internalization, thereby reducing or abolishing short-circuit currents (Qu et al., 2009; Cantin et al., 2006a; Cantin et al., 2006b; Clunes et al., 2012; Sloane et al., 2012; Rasmussen et al., 2014). Reduced CFTR gene transcription rates were mechanistically linked to mobilization of intracellular Ca²⁺, resulting in decreased mRNA and protein expression, presumably in a protein kinase-dependent manner (Bargon et al., 1992a; Bargon et al., 1992b). Cigarette smoke exposure of primary human bronchial epithelial cells at the air-liquid interface was shown to rapidly increase intracellular Ca²⁺, followed by a decrease in cell surface CFTR expression (Rasmussen et al., 2014). Of note, this decrease by CFTR internalization was subsequently linked to decreased active Cl^– transport and a reduction in ASL height/volume (Clunes et al., 2012). Similarly, treatment with pyocyanin, a redox-active virulence factor secreted by Pseudomonas aeruginosa which commonly infects the airways of cystic fibrosis patients, increased hydrogen peroxide levels in CFBE41o- bronchial epithelial cells in a dose- and time-dependent manner, leading to oxidation of the cytosol and inhibited forskolin-stimulated ion transport (Schwarzer et al., 2008). Other possible mechanisms of acquired CFTR dysfunction include direct covalent modification of the protein by cigarette smoke and acrolein (Raju et al., 2013; Raju et al., 2016a) or modulation of channel open probability (Zhang et al., 2013; Woodworth, 2015).

How It Is Measured or Detected

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In cystic fibrosis patients, who carry a defect in the CFTR gene, the determination of the residual levels of normal, full-length CFTR transcripts may have some clinical utility in estimating CFTR function (Amaral et al., 2004). Moreover, decreased CFTR mRNA and protein expression were previously shown to result in reduced CFTR-mediated Cl⁻ transport (Cantin et al., 2006a; Cantin et al., 2006b; Clunes et al., 2012; Sloane et al., 2012; Rasmussen et al., 2014). Therefore, measuring decreased CFTR function could be achieved by a combination of multiple techniques. For example, decreased expression of CFTR mRNA and protein in cells and tissues can be directly assessed using RT-PCR, Northern blot and Western blot or immunocyto-/histochemical methods, respectively. Of note, CFTR gene expression is generally low as is protein abundance, and protein detection methods in general perform more robustly in cultured cells than in native tissues (Farinha et al., 2004). Other, less frequently used methods include cell surface biotinylation, enabling a distinction between intracellular and cell surface forms of the protein if one wishes to study plasma membrane-expressed CFTR. In vitro or ex vivo, CFTR channel function can be assessed in real-time using patch-clamping of whole (single) cells or cell patches. In the whole-cell patch-clamp approach, current flow through CFTR can be assessed by voltage-clamp, whereas current-clamping provides insights into the effects of CFTR currents on membrane voltage (Sheppard et al., 2004). Measuring the efflux of radiolabeled tracers is another means of studying CFTR channel function, permitting a higher throughput than patch-clamping (Norez et al., 2004). The most commonly used method to study CFTR ion transport, however, utilizes the Ussing chamber to measure transepithelial voltage or “active transport potential” and short-circuit current (Li et al., 2004). In vivo, CFTR dysfunction is demonstrated by the chloride sweat test, the gold standard diagnostic tool for cystic fibrosis. The sweat test should be performed according to clinical guidelines using the Gibson and Cooke technique (also known as quantitative pilocarpine iontophoresis sweat test) (Farrell et al., 2017; Smyth et al., 2014). As a complementary diagnostic measure, nasal potential difference (NPD) can be assessed to gauge net transepithelial active ion transport and epithelial ion conductance (Schüler et al., 2004). An entire issue of the Journal of Cystic Fibrosis dedicated to the Virtual Repository of the CFTR Working Group, including the description of consensus research methods, selected principles, techniques and reagents for the assessment of CFTR expression and function is available here: https://www.sciencedirect.com/journal/journal-of-cystic-fibrosis/vol/3/suppl/S2

Domain of Applicability

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Phylogenetic analysis of CFTR DNA sequences across multiple species suggests a close evolutionary relationship between human and primate CFTR, followed by rabbit, guinea pig, equine, ovine, and bovine CFTR, whereas rodent CFTR DNA largely diverges from the human DNA (Chen et al., 2001). Of note, CFTR ion permeability differs from species to species (Higgins, 1992). For example, murine CFTR displays reduced channel activity compared with its human counterpart, while ovine CFTR exhibits higher ATP sensitivity, greater single-channel conductance and larger open probability than human CFTR. Moreover, sensitivity to pharmacological agents able to potentiate or block CFTR gating varies greatly from species to species (Bose et al., 2015). Therefore, results from animal studies are not easily and directly transferable to human.

CFTR dysfunction as a consequence of inherited CFTR gene defects is studied in pediatric as well as adult cystic fibrosis patients. Acquired CFTR dysfunction following inhalation exposures (e.g. to cigarette smoke) may also apply to both pediatric and adult populations, depending on the setting and type of exposure. To our knowledge, the role of gender has not been systematically evaluated in acquired CFTR dysfunction. It is thought that the observed suppression of CFTR expression and impairment of CFTR function in cigarette smokers is a contributing factor to the pathogenesis of chronic obstructive pulmonary disease (COPD) (Dransfield et al., 2013; Raju et al., 2016b). The main risk factor for COPD is cigarette smoking, and COPD is more common in men than in women, which may be directly related to the higher prevalence of smoking in men, although this gender gap is closing (Hitchman and Fong, 2011; Ntritsos et al., 2018; Syamlal et al., 2014). Nevertheless, the available clinical evidence in support of this AOP suggests that there is no remarkable gender difference.

References

List of the literature that was cited for this KE description. More help

Alexander, N.S., Blount, A., Zhang, S., Skinner, D., Hicks, S.B., Chestnut, M., et al., 2012. Cystic fibrosis transmembrane conductance regulator modulation by the tobacco smoke toxin acrolein. The Laryngoscope. 122(6), 1193-1197.
Amaral, M.D., Clarke, L.A., Ramalho, A.S., Beck, S., Broackes-Carter, F., Rowntree, R., et al., 2004. Quantitative methods for the analysis of CFTR transcripts/splicing variants. Journal of Cystic Fibrosis. 3, 17-23.
Bargon, J., Trapnell, B., Yoshimura, K., Dalemans, W., Pavirani, A., Lecocq, J., et al., 1992a. Expression of the cystic fibrosis transmembrane conductance regulator gene can be regulated by protein kinase C. Journal of Biological Chemistry. 267(23), 16056-16060.
Bargon, J., Trapnell, B.C., Chu, C.-S., Rosenthal, E.R., Yoshimura, K., Guggino, W.B., et al., 1992b. Down-regulation of cystic fibrosis transmembrane conductance regulator gene expression by agents that modulate intracellular divalent cations. Molecular and cellular biology. 12(4), 1872-1878.
Bose, S.J., Scott-Ward, T.S., Cai, Z. and Sheppard, D.N., 2015. Exploiting species differences to understand the CFTR Cl− channel. Biochemical Society Transactions. 43(5), 975-982.
Cantin, A.M., Bilodeau, G., Ouellet, C., Liao, J. and Hanrahan, J.W., 2006a. Oxidant stress suppresses CFTR expression. Am J Physiol Cell Physiol. 290(1), C262-270.
Cantin, A.M., Hanrahan, J.W., Bilodeau, G., Ellis, L., Dupuis, A., Liao, J., et al., 2006b. Cystic Fibrosis Transmembrane Conductance Regulator Function Is Suppressed in Cigarette Smokers. American journal of respiratory and critical care medicine. 173(10), 1139-1144.
Chen, J.-M., Cutler, C., Jacques, C., Bœuf, G., Denamur, E., Lecointre, G., et al., 2001. A Combined Analysis of the Cystic Fibrosis Transmembrane Conductance Regulator: Implications for Structure and Disease Models. Molecular Biology and Evolution. 18(9), 1771-1788.
Chinnapaiyan, S., Dutta, R., Bala, J., Parira, T., Agudelo, M., Nair, M., et al., 2018. Cigarette smoke promotes HIV infection of primary bronchial epithelium and additively suppresses CFTR function. Scientific Reports. 8.
Clunes, L.A., Davies, C.M., Coakley, R.D., Aleksandrov, A.A., Henderson, A.G., Zeman, K.L., et al., 2012. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. The FASEB Journal. 26(2), 533-545.
Courville, C.A., Tidwell, S., Liu, B., Accurso, F.J., Dransfield, M.T. and Rowe, S.M., 2014. Acquired defects in CFTR-dependent β-adrenergic sweat secretion in chronic obstructive pulmonary disease. Respiratory research. 15(1), 25.
Dransfield, M.T., Wilhelm, A.M., Flanagan, B., Courville, C., Tidwell, S.L., Raju, S.V., et al., 2013. Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in the Lower Airways in COPD. Chest. 144(2), 498-506.
Farinha, C.M., Penque, D., Roxo-Rosa, M., Lukacs, G., Dormer, R., Mcpherson, M., et al., 2004. Biochemical methods to assess CFTR expression and membrane localization. Journal of Cystic Fibrosis. 3, 73-77.
Farinha, C.M., Matos, P. and Amaral, M.D., 2013. Control of cystic fibrosis transmembrane conductance regulator membrane trafficking: not just from the endoplasmic reticulum to the Golgi. The FEBS Journal. 280(18), 4396-4406.
Farrell, P.M., White, T.B., Ren, C.L., Hempstead, S.E., Accurso, F., Derichs, N., et al., 2017. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. The Journal of Pediatrics. 181, S4-S15.e11.
Hassan, F., Xu, X., Nuovo, G., Killilea, D.W., Tyrrell, J., Da Tan, C., et al., 2014. Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respiratory research. 15(1), 69.
Higgins, C.F., 1992. ABC transporters: from microorganisms to man. Annual review of cell biology. 8(1), 67-113.
Hitchman, S.C. and Fong, G.T., 2011. Gender empowerment and female-to-male smoking prevalence ratios. Bulletin of the World Health Organization. 89(3), 195-202.
Lambert, J.A., Raju, S.V., Tang, L.P., Mcnicholas, C.M., Li, Y., Courville, C.A., et al., 2014. Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis. American journal of respiratory cell and molecular biology. 50(3), 549-558.
Li, H., Sheppard, D.N. and Hug, M.J., 2004. Transepithelial electrical measurements with the Ussing chamber. Journal of Cystic Fibrosis. 3, 123-126.
Norez, C., Heda, G.D., Jensen, T., Kogan, I., Hughes, L.K., Auzanneau, C., et al., 2004. Determination of CFTR chloride channel activity and pharmacology using radiotracer flux methods. Journal of Cystic Fibrosis. 3, 119-121.
Ntritsos, G., Franek, J., Belbasis, L., Christou, M.A., Markozannes, G., Altman, P., et al., 2018. Gender-specific estimates of COPD prevalence: a systematic review and meta-analysis. International journal of chronic obstructive pulmonary disease. 13, 1507.
Qu, F., Qin, X.-Q., Cui, Y.-R., Xiang, Y., Tan, Y.-R., Liu, H.-J., et al., 2009. Ozone stress down-regulates the expression of cystic fibrosis transmembrane conductance regulator in human bronchial epithelial cells. Chemico-Biological Interactions. 179(2–3), 219-226.
Raju, S.V., Jackson, P.L., Courville, C.A., Mcnicholas, C.M., Sloane, P.A., Sabbatini, G., et al., 2013. Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function. American journal of respiratory and critical care medicine. 188(11), 1321-1330.
Raju, S.V., Solomon, G.M., Dransfield, M.T. and Rowe, S.M., 2016a. Acquired CFTR Dysfunction in Chronic Bronchitis and Other Diseases of Mucus Clearance. Clinics in chest medicine. 37(1), 147-158.
Raju, S.V., Lin, V.Y., Liu, L., Mcnicholas, C.M., Karki, S., Sloane, P.A., et al., 2016b. The Cftr Potentiator Ivacaftor Augments Mucociliary Clearance Abrogating Cftr Inhibition by Cigarette Smoke. American journal of respiratory cell and molecular biology.
Raju, S.V., Rasmussen, L., Sloane, P.A., Tang, L.P., Libby, E.F. and Rowe, S.M., 2017. Roflumilast reverses CFTR-mediated ion transport dysfunction in cigarette smoke-exposed mice. Respiratory research. 18(1), 173.
Rasmussen, J.E., Sheridan, J.T., Polk, W., Davies, C.M. and Tarran, R., 2014. Cigarette smoke-induced Ca2+ release leads to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. J Biol Chem. 289(11), 7671-7681.
Rennolds, J., Butler, S., Maloney, K., Boyaka, P.N., Davis, I.C., Knoell, D.L., et al., 2010. Cadmium Regulates the Expression of the CFTR Chloride Channel in Human Airway Epithelial Cells. Toxicological Sciences. 116(1), 349-358.
Riordan, J.R., 2008. CFTR Function and Prospects for Therapy. Annual Review of Biochemistry. 77(1), 701-726.
Schmid, A., Baumlin, N., Ivonnet, P., Dennis, J.S., Campos, M., Krick, S., et al., 2015. Roflumilast partially reverses smoke-induced mucociliary dysfunction. Respiratory research. 16(1), 135.
Schüler, D., Sermet-Gaudelus, I., Wilschanski, M., Ballmann, M., Dechaux, M., Edelman, A., et al., 2004. Basic protocol for transepithelial nasal potential difference measurements. Journal of Cystic Fibrosis. 3, 151-155.
Schwarzer, C., Fischer, H., Kim, E.-J., Barber, K.J., Mills, A.D., Kurth, M.J., et al., 2008. Oxidative stress caused by pyocyanin impairs CFTR Cl− transport in human bronchial epithelial cells. Free Radical Biology and Medicine. 45(12), 1653-1662.
Sheppard, D.N., Gray, M.A., Gong, X., Sohma, Y., Kogan, I., Benos, D.J., et al., 2004. The patch-clamp and planar lipid bilayer techniques: powerful and versatile tools to investigate the CFTR Cl− channel. Journal of Cystic Fibrosis. 3, 101-108.
Sloane, P.A., Shastry, S., Wilhelm, A., Courville, C., Tang, L.P., Backer, K., et al., 2012. A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PloS one. 7(6), e39809.
Smyth, A.R., Bell, S.C., Bojcin, S., Bryon, M., Duff, A., Flume, P., et al., 2014. European Cystic Fibrosis Society Standards of Care: Best Practice guidelines. Journal of Cystic Fibrosis. 13, S23-S42.
Syamlal, G., Mazurek, J.M. and Dube, S.R., 2014. Gender differences in smoking among US working adults. American journal of preventive medicine. 47(4), 467-475.
Woodworth, B.A., 2015. Resveratrol ameliorates abnormalities of fluid and electrolyte secretion in a hypoxia‐Induced model of acquired CFTR deficiency. The Laryngoscope. 125(S7), S1-S13.
Xu, X., Balsiger, R., Tyrrell, J., Boyaka, P.N., Tarran, R. and Cormet-Boyaka, E., 2015. Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR. Biochimica et biophysica acta. 1850(6), 1224-1232.
Zhang, S., Blount, A.C., Mcnicholas, C.M., Skinner, D.F., Chestnut, M., Kappes, J.C., et al., 2013. Resveratrol enhances airway surface liquid depth in sinonasal epithelium by increasing cystic fibrosis transmembrane conductance regulator open probability. PloS one. 8(11), e81589.