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Relationship: 942

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

Activation, Epidermal Growth Factor Receptor leads to Occurrence, Transdifferentiation of ciliated epithelial cells

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Activation, Epidermal Growth Factor Receptor

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Occurrence, Transdifferentiation of ciliated epithelial cells

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

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

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

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

IL13 stimulates transdifferentiation of ciliated epithelial cells to goblet cells through EGFR activation (Tyner et al. 2006), MMP/ADAM (Yoshisue and Hasegawa 2004), p38 MAPK (Fujisawa, et al. 2008) and inhibition of FOXJ1 (Gomperts, et al. 2007). In addition to IL13, IL4 has been shown to act through shared receptor IL4RA to stimulate goblet cell differentiation and inhibit ciliogenesis (Laoukili, et al. 2001). IL4 and IL13 but not IL5 or IL9 have been shown to induce goblet cell metaplasia in mouse trachial epiethelial cells (Fujisawa, et al. 2008).

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

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

There is biological plausibility of ciliated cell transdifferentiation to goblet cells as a number of studies have shown a mix of features characteristic of each cell type within a cell (Tyner, et al. 2006, Laoukili, et al. 2001, Gomperts et al. 2007) or fluorescent labeling from ciliated cells detected in goblet cells after differentiation (Turner et al. 2011).

However, ciliated cell transdifferentiation remains controversial in terms of napthalene or sulfur dioxide-induced injury with conflicting reports for lack of transdifferentiation (Rawlins, et al. 2006) and evidence for transdifferentiation (Van Winkle, et al. 1995; Lawson, et al. 2002, Park, et al. 2006).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Include consideration of temporal concordance here

In cultured 3D differentiated human airway epithelial tissue, 50 or 100ng/mL IL13 induced transdifferentiation of ciliated to goblet cells after 3 days, measured by decreased FOXJ1 and loss of ezrin and basal bodies, features of ciliated cells and increase of MUC5AC protein, a marker for goblet cells (Gomperts 2007).

In cultured human bronchial epithelial cells, goblet cells were derived from ciliated cells after 1 ng/mL IL13 treatment for 28-35 days shown by green fluorescent labeling (Turner 2011).

In cultured human bronchial epithelial cells, 20ng/mL IL13 for 14 days increased goblet cell and decreased ciliated cell gene markers, and increased mucus production via MMP/ADAM (Yoshisue 2004). Accompanying increase in EGFR ligand TGFA indicates the EGFR pathway was involved in IL13-induced ciliat to goblet differentiation.

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

IL13-induced goblet cell increase has been shown to be concentration-dependent in human bronchial epithelial cells with 1ng/ml inducing and 10ng/ml suppressing goblet cell increase (Atherton, et al. 2003), however multiple studies have shown that concentrations from 5-100ng/mL do induce goblet cell hyperplasia, including in human bronchial epithelial cells (Yoshisue 2004).

It has been shown that two weeks but not one week of human nasal epithelial cell differentiation and IL13 treatment showed a decrease in proportion of ciliated cells (shown by glutamylated tubulin protein expression) (Laouikili 2001), however other studies showed that IL13-induced ciliated to goblet cell differentiation were observed in as little as 3-5 days cultured human airway epithelium, mouse tracheal epithelial cells and a Sendai virus mouse model (Gomperts 2007, Fujisawa 2008, Tyner 2006). This difference may be due to the difference in cell types used in these experiments. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge for 48 hours which may be due to insufficient time for OVA-induced IL13 upregulation and subsequent effects (Pardo-Saganta 2013).

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

It has been proposed that the effects of IL13 and IL4 on differentiation to goblet cells is concentration-dependent in human bronchial epithelial cells, with 1ng/ml inducing an increase in goblet cell density acting through MAPK and p38 MAPK but not EGFR and 10ng/ml inducing a reduction in goblet cell density (Atherton et al. 2003). Other studies have agreed with this finding, with 1ng/mL IL13 leading to an increase in goblet hyperplasia in human bronchial epitehlial cells (Turner 2011) and 5ng/mL having a lack of effect inducing goblet cell differentiation in nasal epithelial cells (Kim 2002). On the contrary, multiple studies have shown that concentrations from 5-100ng/mL do induce goblet cell hyperplasia in human bronchial epithelial cells, human nasal epithelial cells, cultured human differentiated airway epithelial tissue, cultured guinea pig tracheal epithelium, and mouse tracheal epithelial cells (Yoshisue 2004, Laouikili 2001, Gomperts 2007, Kondo 2002, Fujisawa 2008).

It has also been proposed that two weeks of differentiation is necessary to see the effects (Laouikili 2001) and could explain why differentiation was not observed in a two day OVA-induced murine model (Pardo-Saganta 2013) or seven day human nasal epithelial cell model (Kim 2002). On the contrary, IL13-induced goblet cell metaplasia was also observed in short term experiments of 3-5 days in cultured human airway epithelium, mouse tracheal epithelial cells and a Sendai virus mouse model (Gomperts 2007, Fujisawa 2008, Tyner 2006).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

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

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

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 demonstrating transdifferentiation from ciliated to goblet cells including in 3D human airway epithelial models (Gomperts et al. 2007), human 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).

Two mouse studies have demonstrated transdifferentiation and goblet metaplasia (Tyner, et al. 2006, Fujisawa, et al. 2008) while another mouse study has shown that ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge (Pardo-Saganta, et al. 2013), however this could be due to the short 48 hour time point which has been noted is not enough time for transdifferentiation (Laoukili, et al. 2001).

Rat studies have demonstrated IL-13 and/or EGFR involvement in goblet cell metaplasia/hyperplasia, however no rat studies have directly measured transdifferentiation of ciliated to goblet cells to our knowledge (Shim 2001, Takeyama 2008).

References

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