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Event: 1906

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Cystic Fibrosis Transmembrane Regulator Function, Decreased

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
CFTR Function, Decreased

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term
epithelial cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. 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 Arthur Author (send email) Open for comment. Do not cite


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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:   

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

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.

Evidence for Perturbation by Stressor


Acrolein exhibited a complex dose-dependent response with respect to CFTR-mediated Cl transport in primary murine nasal septal epithelia: At 100 µM acrolein, Cl currents increased, whereas 300 µM acrolein reduced forskolin-induced total apical Cl secretion and 300 µM acrolein abolished all Cl transport. These effects were independent of cAMP, suggesting that channel activation was not PKA/cAMP phosphorylation-dependent (Alexander et al., 2012). Acrolein decreased cAMP-mediated CFTR ion transport in human bronchial epithelial cells grown in monolayers and in human Calu-3 lung cancer cells, where the response was dose-dependent. Repeated, low-level exposure of human bronchial epithelial cells to acrolein (2.5 – 10 ng/mL for 7 days) had a similar effect on CFTR function and was shown to be unrelated to modulation of CFTR expression. Pretreatment with the antioxidant N-acetylcysteine could prevent acrolein-induced CFTR inhibition (Raju et al., 2013). Similar effects on CFTR function (as measured by nasal and intestinal transepithelial potential difference) were elicited by subcutaneous administration of 1 mg/kg acrolein for 4 weeks, and these could also be counteracted by co-treatment with NAC (Raju et al., 2013).


Tracheas of Wistar rats exposed to 1.5 ppm ozone for 1 h/day for 3 days exhibited reduced CFTR protein expression. Similarly, at 4 hours following a 30-min exposure to ozone, CFTR mRNA and protein were down-regulated in 16HBE14o- cells. At 24 hours post-exposure, a reduction in forskolin-stimulated CFTR Cl− conductance was observed (Qu et al., 2009).

Cigarette smoke

CFTR transcript and protein levels were reduced in human Calu-3 lung cancer cells exposed to the gas phase of cigarette smoke (Cantin et al., 2006b), human immortalized bronchial epithelial 16HBE14o- cells treated with 10% cigarette smoke extract (Hassan et al., 2014; Rasmussen et al., 2014; Xu et al., 2015), differentiated primary human bronchial epithelial cells exposed to whole cigarette smoke (Sloane et al., 2012; Hassan et al., 2014), and in airways of smokers compared to non-smokers (Dransfield et al., 2013). Following exposure to cigarette smoke, Cl conductance (i.e., CFTR-mediated Cl transport) decreased in primary human bronchial epithelial cells grown in monolayers (Lambert et al., 2014), differentiated primary human bronchial epithelial cells (Schmid et al., 2015; Chinnapaiyan et al., 2018), and nasal respiratory and intestinal epithelia of A/J mice (Raju et al., 2013; Raju et al., 2017). In the lower airways, healthy smokers and smokers with chronic obstructive pulmonary disease (COPD) showed reduced CFTR-dependent Cl transport, whereas COPD former smokers showed an intermediate response to chloride-free isoproterenol solution compared to non-smokers. Similarly, amiloride-sensitive lower airway potential difference was also lower in healthy smokers and COPD smokers than in healthy non-smokers. This was linked to reduced CFTR protein levels in the airways of smokers compared to non-smokers, although there were no significant differences between healthy and COPD subjects (Dransfield et al., 2013). CFTR-dependent Cl conductance as measured by nasal potential difference was also significantly reduced in healthy and COPD smokers compared to healthy non-smokers or to former smokers with COPD (Sloane et al., 2012). In addition, healthy never-smokers had higher mean sweat chloride concentrations than COPD smokers and COPD former smokers (Raju et al., 2013; Courville et al., 2014).


Cadmium (Cd) decreased CFTR protein expression in Calu-3 cells in a dose- and time-dependent manner. CFTR transcript levels, however, appeared to only be transiently affected. Reduced CFTR expression at the plasma membrane was associated with a reduction in CFTR Cl conductance. Treatment of cells with NAC did not rescue CFTR expression in Cd-treated cells. In contrast, co-treatment with α-tocopherol prevented CFTR inhibition, and this effect was linked to α-tocopherol suppressing the accumulation of ubiquitinated CFTR (Rennolds et al., 2010).


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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.