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Relationship: 2470

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

Decreased ciliated cell apoptosis leads to Goblet cell metaplasia

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Decreased ciliated cell apoptosis
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Goblet cell metaplasia

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 Low 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 Do not cite Under Development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 Moderate 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 Low

Life Stage Applicability

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

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

Following injury, airway epithelial repair is accomplished by (transient) remodeling processes. In the absence of cell proliferation, this remodeling is thought to be facilitated by 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). This transdifferentiation results in what pathologists refer to as goblet cell metaplasia.

Transdifferentiation frequently occurs following airway epithelial injury by inhalation exposures (e.g. cigarette smoke, sulfur dioxide, endotoxin, viruses). Subsequent tissue repair processes are thought to initiate the transdifferentiation process, whereby ciliated epithelial cells first dedifferentiate and then redifferentiate to goblet cells, without an apparent increase in the total number of epithelial cells (Lumsden et al., 1984; Shimizu et al., 1996; Reader et al., 2003). Alternatively, transdifferentiation may occur following the activation of EGFR-mediated anti-apoptotic signaling in ciliated epithelial cells. Subsequent stimulation by proinflammatory stimuli such as the Th2 cytokines interleukin (IL)-4 and IL-13 then promotes transdifferentiation of ciliated cells into goblet cells, thereby increasing the number of goblet cells (“second hit hypothesis”) in mouse tracheal epithelium and airway epithelia of COPD patients (Laoukili et al., 2001; Tyner et al., 2006; Curran and Cohn, 2010).

 

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

There is no direct evidence linking decreased apoptosis in ciliated cells to their transdifferentiation, because these events were not systematically examined yet. Co-localization of EGFR and β-tubulin, a ciliated cell marker, but not CCSP (secretory cell marker) or MUC5AC (goblet cell marker) expression was observed in mouse airways 21 days after inoculation with Sendai virus and in the airways of asthma patients (Tyner et al., 2006; Takeyama et al., 2001). In addition, ciliated cell tagging studies in vitro indicated that the number of ciliated cells decreases following treatment with IL-13, while the number of goblet cells increases (Turner et al., 2011). Together these studies are supportive of transdifferentiation of ciliated cells, sustained by anti-apoptotic signaling, into goblet cells.   

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

While the evidence linking decreased apoptosis in ciliated cells to their transdifferentiation is indirect or correlative (Tyner et al., 2006; Silva and Bercik, 2012; Reader et al., 2003; Turner et al., 2011; Ayers et al., 1988; Jefferey et al., 1984), decreased ciliated cell apoptosis following exposure may imply that a (numerically stable) pool of cells is available for IL-13- and/or IL-4-mediated transdifferentiation to goblet cells (Curran and Cohn, 2010). Therefore, our confidence in the biological plausibility of this KER is low.  

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

Experimental evidence in support of this KER is not in agreement with other studies, which show that ciliated cells do not give rise to goblet cells during airway remodeling in rodents and humans, and with studies that provide evidence for increased goblet cell proliferation rather than transdifferentiation of ciliated cells (Lumsden et al., 1984; Casalino-Matsuda et al., 2006; Hays et al., 2006; Tesfaigzi et al., 2004; Taniguchi et al., 2001).  

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

Treatment of mouse tracheal epithelial cells, differentiated at the air-liquid interface, with IL-13 (100 ng/mL for 5 days) to stimulate goblet cell formation and subsequently with PD153035 (0.3 μM for 3 days) to block EGFR activation did have no significant effect on the rate of apoptosis in Muc5ac-positive cells, whereas the ciliated epithelial cells exhibited significant caspase-positive staining (increased by ca. 10%) (Tyner et al., 2006).

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

Treatment of mouse tracheal epithelial cells, differentiated at the air-liquid interface, with IL-13 (100 ng/mL for 5 days) to stimulate goblet cell formation gave rise to a transitional cell population. These transitional cells were most prominent early (1–2 days) after initiation of IL-13 treatment, while mature goblet cells without cilia were most abundant at later times (5 days) after treatment. The same observation of transitional cells showing both goblet and ciliated cell marker expression was made in airway epithelial cells cultured from COPD patients and from otherwise healthy lung transplant donors in response to IL-13, within the first day of IL-13 treatment (Tyner et al., 2006).  

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

There are many human studies illustrating transdifferentiation from ciliated to goblet cells or goblet cell metaplasia in 3D airway epithelial models (Gomperts et al., 2007), bronchial or nasal epithelial cells in vitro (Yoshisue and Hasegawa 2004, Turner et al., 2011, Laoukili et al., 2001) and in COPD patients (Tyner et al., 2006). Airway epithelial transdifferentiation and goblet metaplasia were also observed in mice (Tyner et al., 2006, Fujisawa et al., 2008) and in rats (Shim et al., 2001; Takeyama et al., 2008). However, to our knowledge, none of these studies measured transdifferentiation of ciliated to goblet cells directly.  

References

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

Ayers, M., and Jeffery, P. (1988). Proliferation and differentiation in mammalian airway epithelium. Eur. Respir. J. 1, 58-80.

Casalino-Matsuda, S.M., Monzón, M.E., and Forteza, R.M. (2006). Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am. J. Resp. Cell Mol. Biol. 34, 581-591.

Curran, D.R., and Cohn, L. (2010). Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am. J. Resp. Cell Mol. Biol. 42, 268-275.

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. 

Hays, S.R., and Fahy, J.V. (2006). Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. Am. J. Resp. Crit. Care Med. 174, 1018-1024.

Jefferey, P., Rogers, D., Ayers, M., and Shields, P. (1984). Structural aspects of cigarette smoke-induced pulmonary disease. In Smoking and the Lung (Springer), pp. 1-31.

Lamb, D., and Reid, L. (1968). Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during exposure to sulphur dioxide. J. Pathol. Bacteriol. 96, 97-111.

Laoukili, J., Perret, E., Willems, T., Minty, A., Parthoens, E., Houcine, O., et al. (2001). IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J. Clin. Invest. 108, 1817-1824. 

Lumsden, A.B., McLean, A., and Lamb, D. (1984). Goblet and Clara cells of human distal airways: evidence for smoking induced changes in their numbers. Thorax 39, 844-849.

Reader, J.R., Tepper, J.S., Schelegle, E.S., Aldrich, M.C., Putney, L.F., Pfeiffer, J.W., and Hyde, D.M. (2003). Pathogenesis of mucous cell metaplasia in a murine asthma model. Am. J. Pathol. 162, 2069-2078.

Shimizu, T., Takahashi, Y., Kawaguchi, S., and Sakakura, Y. (1996). Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. Am. J. Respir. Crit. Care Med. 153, 1412-1418.

Silva, M.A., and Bercik, P. (2012). Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells. Lab. Invest. 92, 937-948.

Takeyama, K., Fahy, J., and Nadel, J. (2001). Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am. J. Resp. Crit. Care Med. 163, 511-516.

Taniguchi, K., Yamamoto, S., Aoki, S., Toda, S., Izuhara, K., and Hamasaki, Y. (2011). Epigen is induced during the interleukin-13–stimulated cell proliferation in murine primary airway epithelial cells. Exp. Lung Res. 37, 461-470.

Tesfaigzi, Y., Harris, J.F., Hotchkiss, J.A., and Harkema, J.R. (2004). DNA synthesis and Bcl-2 expression during development of mucous cell metaplasia in airway epithelium of rats exposed to LPS. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L268-L274.

Tesfaigzi, Y., Harris, J.F., Hotchkiss, J.A., and Harkema, J.R. (2004). DNA synthesis and Bcl-2 expression during development of mucous cell metaplasia in airway epithelium of rats exposed to LPS. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L268-L274. 

Turner, J., Roger, J., Fitau, J., Combe, D., Giddings, J., Heeke, G.V., and Jones, C.E. (2011). Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium. Am. J. Resp. Cell Mol. Biol. 44, 276-284.

Tyner, J.W., Kim, E.Y., Ide, K., Pelletier, M.R., Roswit, W.T., Morton, J.D., Battaile, J.T., Patel, A.C., Patterson, G.A., Castro, M., et al. (2006). Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J. Clin. Invest. 116, 309-321.

Yoshisue, H., and Hasegawa, K. (2004). Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Biosci. Biotech. Biochem. 68, 2024-2031.