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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

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

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

There is no considerable quantitative understanding of the linkage yet.

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.