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Relationship: 1962

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

Frustrated phagocytosis leads to Release, Cytokine

Upstream event

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

Frustrated phagocytosis

Downstream event

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

Release, Cytokine

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
Frustrated phagocytosis-induced lung cancer	adjacent			Carole Seidel (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 Do not cite	Under Development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
mammals	mammals		NCBI

Sex Applicability

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

Sex	Evidence
Unspecific

Life Stage Applicability

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

Term	Evidence
Adult

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

Phagocytosis allow the clearance of foreign matter. Incomplete phagocytosis, or frustrated phagocytosis, leads to the persistence of foreign matter. Therefore, in order to clear these substances, phagocytes secretes signals including cytokines for the recruitment of other phagocytes.

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

The main function of professional phagocytes is to clear the tissue of the foreign matter by phagocytosis [1]. Following exposure to foreign matter, macrophages are activated and therefore secrete pro-inflammatory mediators including cytokines [1].

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

In the study of Murphy et al, the human monocytic THP-1 cells treated with carbon nanotubes (CNTs) that induce frustrated phagocytosis showed an increase production of IL-1β, IL-6 and IL-8 whereas treatment by CNTs that did not induce this process did not induce production of these cytokines [2]. Similarly, it was shown that exposure to fibres that induced frustrated phagocytosis of primary human alveolar macrophages is accompanied by induction of IL-6 and IL-8 [3], and exposure of immortalized MH-S murine alveolar macrophage is accompanied by induction of TNFα and IL-1α [4, 5]. The induction of cytokines was observed in lesser extend after cell treatment with fibres that did not cause frustrated phagocytosis. Indeed, the ratio of the dose-response for TNFα and IL-1α of long fibres to short fibres was about 11 [4, 5].

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

In very few studies it was analysed the release of cytokines in the same samples as the frustrated phagocytosis.

A study of Zeidler-Erdely et al 2006 showed that human alveolar macrophages are able to engulf fibres with a length of 20 µm and explained this difference with rat alveolar macrophages are smaller than human cells [6]. However, these data are not in accordance with those obtained by Sweeney et al 2015 were they used primary human alveolar macrophages and by Murphy et al 2012 were they used monocytic cells THP-1 differentiated in macrophages [2, 3].

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

Response-response Relationship

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

The length of fibres that induced frustrated phagocytosis accompanied by cytokines production were comprised between 13 and 39.3 µm, whereas fibres with length between 1 and 7 µm were completely phagocytosed and did not induce cytokine production [2, 3, 4].

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

The frustrated phagocytosis and cytokine production were observed after 16 to 24h of treatment [2, 3, 4, 5].

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

References

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

1. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. 2011;11 11:723-37; doi: 10.1038/nri3073.

2. Murphy FA, Schinwald A, Poland CA, Donaldson K. The mechanism of pleural inflammation by long carbon nanotubes: interaction of long fibres with macrophages stimulates them to amplify pro-inflammatory responses in mesothelial cells. Particle and fibre toxicology. 2012;9:8; doi: 10.1186/1743-8977-9-8.

3. Sweeney S, Grandolfo D, Ruenraroengsak P, Tetley TD. Functional consequences for primary human alveolar macrophages following treatment with long, but not short, multiwalled carbon nanotubes. International journal of nanomedicine. 2015;10:3115-29; doi: 10.2147/IJN.S77867.

4. Padmore T, Stark C, Turkevich LA, Champion JA. Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages. Biochimica et biophysica acta. 2017;1861 2:58-67; doi: 10.1016/j.bbagen.2016.09.031.

5. Ye J, Shi X, Jones W, Rojanasakul Y, Cheng N, Schwegler-Berry D, et al. Critical role of glass fiber length in TNF-alpha production and transcription factor activation in macrophages. 1999;276 3:L426-34; doi: 10.1152/ajplung.1999.276.3.L426.

6. Zeidler-Erdely PC, Calhoun WJ, Ameredes BT, Clark MP, Deye GJ, Baron P, et al. In vitro cytotoxicity of Manville Code 100 glass fibers: effect of fiber length on human alveolar macrophages. 2006;3:5; doi: 10.1186/1743-8977-3-5.