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Relationship: 2471

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Goblet cell metaplasia leads to Chronic, Mucus hypersecretion

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). 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

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 Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. 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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. 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
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field 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.   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
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. 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).  

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Unknown

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  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).  

Time-scale
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?). 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 Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Unknown

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. 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.