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Relationship: 2471


The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Goblet cell metaplasia leads to Chronic, Mucus hypersecretion

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
EGFR Activation Leading to Decreased Lung Function adjacent Moderate Moderate Karsta Luettich (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages Moderate

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Goblet cell metaplasia refers to the result of transdifferentiation, i.e., the generation of specialized cell types, such as goblet cells, from other specialized cells, such as ciliated and club cells (Evans et al., 2004; Tesfaigzi, 2006), and is a key feature of the chronically remodeled airways in both asthma and COPD (Kuchibhotla and Heijink, 2020). Chronic mucus hypersecretion is also a main feature of chronic lung diseases, and the presence of goblet cell metaplasia in the lungs of chronic obstructive pulmonary disease, asthma and cystic fibrosis patients has been inferred as cause for sustained mucus production (Rose and Voynow, 2006; Boucherat et al., 2013; Munkholm and Mortensen, 2014).  

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

This KER is inferred. However, several studies provide concomitant data on histopathologically identified goblet cell metaplasia and increased mucus content or mucin production.  

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

This KER is inferred. However, that an increase in goblet cell numbers also increases mucin production is highly plausible. Studies in human cells, mice and rats demonstrate that mucin content or MUC5AC mRNA and protein expression increase in the presence of histologically confirmed goblet cell metaplasia. Because both events are measured in parallel and causal evidence is missing, our confidence is moderate.    

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

In some cases, it appears that authors use the terms "goblet cell hyperplasia" and "goblet cell metaplasia" interchangeably, making the evaluation of the available evidence difficult.  

Because goblet cell metaplasia is also a feature of epithelial cell remodeling in the context of wound healing, its appearance can be transient. At least one study indicates that goblet cell hyperplasia is also found in healthy non-smokers (never- and former smokers), where it appears as isolated foci—as opposed to the more extensive involvement of the airway epithelium seen in e.g. COPD patients (Polosukhin et al., 2011).  

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help

Daily 30-min treatments of primary human bronchial epithelial cells at the air-liquid interface with 0.6 mM xanthine and 0.5 units xanthine oxidase for 3 days resulted in goblet cell metaplasia as evidenced by an increase in the numbers of MUC5AC-positive cells from 3.3 ± 1.2%to 21.6 ± 3.4%, and increased MUC5AC protein expression (32.5 + 9.3% above PBS control) (Casalino-Matsuda et al., 2006).

Intranasal insitillation of 0.1 mg LPS (E.coli 0111:B4) once a day for 3 consecutive days induced goblet cell metaplasia in the nasal epithelium (as judged by histopathology), with an approx. 50% increase in AB/PAS-stained epithelium compared to untreated controls (Takezawa et al., 2016).

Induction of airway inflammation with 50 µg house dust mite (1.27 endotoxin units/mg) for 5 days/week for 6 weeks resulted goblet cell metaplasia as evidenced by extensive AB staining in the animals' airways (Le Cras et al., 2011). Using the same model with a 3-week treatment demonstrated goblet cell metaplasia as judged by increased PAS staining in the airway epithelium and ca. 10-, 5-, and 4-fold increases in expression of goblet cell metaplasia-related genes Muc5ac, Clca1, and Postn, respectively (Habibovic et al., 2016).

Pyocyanin, a redox-active exotoxin of Pseudomonas aeruginosa, caused goblet cell metaplasia in C57Bl/6 mice after 3-week treatment (25 µg/day). PAS staining increased by ca. 30%; the percentage of Muc5ab-positive cell in bronchial epithelium increased 6.4-fold and in bronchiolar epithelium 11.4-fold (Hao et al., 2012).

Male Sprague–Dawley rats that were exposed to 3 ppm acrolein for 6 h a day, for 12 days developed goblet cell metaplasia (as judged by histopathology), increasing the % AB/PAS-positive stained epithelium from ca. 5% (in air controls) to 35%. This was accompanied by a nearly 15% increase in Muc5ac-positive stained cells, a ca. 3-fold increase in Muc5ac mRNA expression and a ca. 4-fold increase in protein expression (Chen et al., 2010).

Exposure of female Sprague-Dawley rats to wood smoke (40 g of China fir sawdust was smoldered) for 1 h four times per day, five days per week, for three months caused goblet cell metaplasia in the airways (as judged by histopathology), a 2-fold increase in Muc5ac gene expression, an increase in the % AB/PAS-positive stained epithelium from approx. 6% (air controls) to ca. 17%, an increase in Muc5ac-positive stained cells from approx. 5% (air controls) to ca. 25%  (Huang et al., 2017).

Exposure of male Sprague-Dawley rats to smoke from five cigarettes (2R4F, University of Kentucky) a day for 5 days resulted in goblet cell metaplasia in the airways (as judged by histopathology) and an approx. 70% increase in AB/PAS-stained epithelium (Lee et al., 2006).

Intratracheal instillation of LPS (P. aeruginosa serotype 10; 200 or 300 μg in 300 μL PBS) in male Sprague-Dawley rats caused goblet cell metaplasia in the airways, with 42.31 ± 3.36, 45.46 ± 2.24, and 63.13 ± 4.6% AB/PAS-positive staining at 3, 5, and 7 days after low-dose LPS instillation, respectively, and 71.6 ± 2.56% AB/PAS-positive staining at 7 days after high-dose LPS instillation. MUC5AC protein expression in the bronchial epithelium of the control and LPS groups (300 μg, 7 days post-instillation) were 5.46 ± 4.68 and 75.32 ± 4.53, respectively (Kim et al., 2004).  

This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help

Instillation of agarose plugs (0.7-0.8 mm diameter, 4% agarose II) in Fischer rats caused a time-dependent increase in goblet cell area (by AB/PAS staining), which was detectable as early as 24 h and was greatest 72 h post-instillation. The AB/PAS-stained area increased from 0.1 ± 0.1% in control animals to 4.7 ± 1.4, 13.3 ± 0.7, and to 19.1 ± 0.7% at 24, 48, and 72 h post-instillation, respectively. Goblet cell numbers increased from 0 to 13.1 ± 5.6, 25.7 ± 15.0, and 51.5 ± 9.0 cells/mm basal lamina at 24, 48, and 72 h post-instillation, respectively (Lee et al., 2000).

Intratracheal instillation of LPS (P. aeruginosa serotype 10; 200 or 300 μg in 300 μL PBS) in male Sprague-Dawley rats caused goblet cell metaplasia in the airways, with 42.31 ± 3.36, 45.46 ± 2.24, and 63.13 ± 4.6% AB/PAS-positive staining at 3, 5, and 7 days after low-dose LPS instillation, respectively, and 71.6 ± 2.56% AB/PAS-positive staining at 7 days after high-dose LPS instillation. MUC5AC protein expression in the bronchial epithelium of the control and LPS groups (300 μg, 7 days post-instillation) were 5.46 ± 4.68 and 75.32 ± 4.53, respectively (Kim et al., 2004).  

Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help


Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help


Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help


List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Boucherat, O., Boczkowski, J., Jeannotte, L., and Delacourt, C. (2013). Cellular and molecular mechanisms of goblet cell metaplasia in the respiratory airways. Exp. Lung Res. 39, 207-216.

Casalino-Matsuda, S.M., Monzon, M.E., Conner, G.E., Salathe, M., and Forteza, R.M. (2004). Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated epidermal growth factor receptor activation in human airways. J. Biol. Chem. 279, 21606-21616. 

Chen, Y.-J., Chen, P., Wang, H.-X., Wang, T., Chen, L., Wang, X., et al. (2010). Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway. Intl. Immunopharmacol. 10, 685-693.

Evans, C.M., Williams, O.W., Tuvim, M.J., Nigam, R., Mixides, G.P., Blackburn, M.R., et al. (2004). Mucin Is produced by Clara cells in the proximal airways of antigen-challenged mice. Am. J. Respir. Cell Mol. Biol. 31, 382-394. 

Habibovic, A., Hristova, M., Heppner, D.E., Danyal, K., Ather, J.L., Janssen-Heininger, Y.M., et al. (2016). DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma. JCI Insight 1, e88811.

Hao, Y., Kuang, Z., Xu, Y., Walling, B.E., and Lau, G.W. (2013). Pyocyanin-induced mucin production is associated with redox modification of FOXA2. Respir. Res. 14, 82-82. 

Huang, L., Pu, J., He, F., Liao, B., Hao, B., Hong, W., et al. (2017). Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2.5 from wood smoke-induced MUC5AC expression in epithelial cells. Sci. Rep. 7, 11084. 

Kim, J.H., Lee, S.Y., Bak, S.M., Suh, I.B., Lee, S.Y., Shin, C., et al. (2004b). Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L127-L133. 

Kuchibhotla, V.N.S., and Heijink, I.H. (2020). Join or Leave the Club: Jagged1 and Notch2 Dictate the Fate of Airway Epithelial Cells. Am. J. Respir. Cell Mol. Biol. 63, 4-6.

Le Cras, T.D., Acciani, T.H., Mushaben, E.M., Kramer, E.L., Pastura, P.A., Hardie, W.D., et al. (2011). Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L414-L421.

Lee, H.-M., Takeyama, K., Dabbagh, K., Lausier, J.A., Ueki, I.F., and Nadel, J.A. (2000). Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L185-L192.

Lee, S.Y., Kang, E.J., Hur, G.Y., Jung, K.H., Jung, H.C., Lee, S.Y., et al. (2006). The inhibitory effects of rebamipide on cigarette smoke-induced airway mucin production. Respir. Med. 100, 503-511.

Munkholm, M., and Mortensen, J. (2014). Mucociliary clearance: pathophysiological aspects. Clin. Physiol. Funct. Imaging 34, 171-177.

Polosukhin, V.V., Cates, J.M., Lawson, W.E., Milstone, A.P., Matafonov, A.G., Massion, P.P., et al. (2011). Hypoxia‐inducible factor‐1 signalling promotes goblet cell hyperplasia in airway epithelium. J. Pathol. 224, 203-211.

Rose, M.C., and Voynow, J.A. (2006). Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev. 86, 245-278.

Takezawa, K., Ogawa, T., Shimizu, S., and Shimizu, T. (2016). Epidermal growth factor receptor inhibitor AG1478 inhibits mucus hypersecretion in airway epithelium. Am. J. Rhinol. Allergy 30, e1-e6.

Tesfaigzi, Y. (2006). Roles of apoptosis in airway epithelia. Am. J. Respir. Cell Mol. Biol. 34, 537-547.