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Relationship: 990

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 Hypersecretion, Mucus

Upstream event

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

Goblet cell metaplasia

Downstream event

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

Hypersecretion, Mucus

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
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI
human	Homo sapiens	High	NCBI

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

Goblet cell metaplasia results in an increased number of goblet cells and secretion of mucus. This can lead to mucus hypersecretion, narrowing of airways and difficulty breathing (Nadel, 2013). There is an inverse relationship between goblet cell metaplasia and FEV1, a measure of lung function (Nagai et al., 1995). Smokers have an increased number of goblet cells in peripheral airways which is negatively correlated with low FEV1/FVC (lung function) which could be caused by mucus hypersecretion (Saetta et al., 2000).

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

It is biologically plausible that increased metaplasia leads to mucus hypersecretion. The increased number of goblet cells in metaplastic tissue secrete increased mucus. Studies have found low mitotic rates along with increased number of goblet cells, suggesting differentiation into and not proliferation of goblet cells is occurring (Shimizu et al., 1996), (Lamb and Reid, 1968).

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

There is no empirical support since clinical studies do not investigate cellular differentiation into goblet cells and functional measures of mucus hypersecretion within the same study.

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

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?

The KEs in this relationship are considered equivalent in most animal studies (increased mucus is a measure for metaplasia as well as mucus hypersecretion). A study measuring differentiated goblet cells and the relationship to increased mucin production would add to the quantitative understanding of how much mucus is produced per differentiated goblet cell. A clinical study measuring increased mucus in the lung and the relationship to sputum production would add to the quantitative understanding of how internal mucus relates to sputum production, however it would be unclear whether increased mucus is due to hyperplasia or metaplasia unless proliferation and differentiation is specifically tested.

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

Many studies have shown metaplasia and mucus hypersecretion in human, mouse and rat. Studies show a correlative relationship rather than a causal one, and sometimes these terms are used synonymously.

References

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

1. 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.

2. Nadel, J. (2013). Mucous hypersecretion and relationship to cough. Pulm Pharmacol Ther 26, 510–513.

3. Nagai, A., Thurlbeck, W.M., and Konno, K. (1995). Responsiveness and variability of airflow obstruction in chronic obstructive pulmonary disease. Clinicopathologic correlative studies. Am. J. Respir. Crit. Care Med. 151, 635–639.

4. Saetta, M., Turato, G., Baraldo, S., Zanin, A., Braccioni, F., Mapp, C., Maestrelli, P., Cavallesco, G., Papi, A., and Fabbri, L. (2000). Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 161, 1016–1021.

5. 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.