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Relationship: 942


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
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

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).

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


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