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Relationship: 2777

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

Increased pro-inflammatory mediators leads to Increase, Endothelial Dysfunction

Upstream event

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

Increased pro-inflammatory mediators

Downstream event

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

Increase, Endothelial Dysfunction

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
Deposition of energy leads to vascular remodeling	adjacent	Moderate	Low	Cataia Ives (send email)	Open for citation & comment

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	Low	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Low	NCBI

Sex Applicability

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

Sex	Evidence
Male	Moderate
Female	Low
Unspecific	Low

Life Stage Applicability

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

Term	Evidence
Adult	Low
Juvenile	Moderate

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

An increase in pro-inflammatory mediators including the cytokines tumor necrosis factor-α (TNF-α), interleukin 1 beta and 6 (IL-1β, IL-6), chemokines monocyte chemoattractant protein 1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) can lead to inflammatory response which can disrupt cellular homeostasis and if persistent can lead to eventual endothelial dysfunction (Venkatesulu et al., 2018; Korpela & Liu, 2014). Normally, an inflammatory response provides a protective effect to the endothelium but if prolonged (over months) it can exhaust this protective inflammatory effect, as a result, endothelial cells may become senescent or apoptotic, leading to endothelial dysfunction (Deanfield et al., 2007; Bonetti et al., 2003, Wang et al., 2016; Hughson et al., 2018; Ramadan et al., 2021).

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

The strategy for collating the evidence on radiation stressors to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

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

Much of the evidence for this relationship comes from in vitro studies; further work is needed to determine the certainty of the relationship at the tissue level.
Although studies often measure pro-inflammatory mediators at a few specific time points, chronic inflammation is what contributes to endothelial dysfunction. More human studies should examine the temporal concordance of this relationship to identify whether the inflammation is chronic.

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

Modulating factor	Details	Effects on the KER	References
Drug	TAT-Gap19 (connexin 43 hemichannel blocker)	Attenuated the radiation-induced increase of many pro-inflammatory mediators and SA-β-gal activity.	(Ramadan et al., 2020)
Media	Mesenchymal stem cell conditioned media	The increase in various pro-inflammatory mediators and apoptosis was reduced.	(Chang et al., 2017)

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

The following are a few examples of quantitative understanding of the relationship. All data that is represented is statistically significant unless otherwise indicated.

Response-response Relationship

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

Dose/Incidence Concordance

Reference	Experiment Description	Result
Baselet et al., 2017	In vitro. Telomerase immortalized human coronary artery endothelial cells (TICAE) were irradiated with X-rays in the range of 0.05-2 Gy at a dose rate of 0.50 Gy/min.	Pro-inflammatory mediators CCL2 and IL-6 show a slight but non-significant increase at 0.05 and 0.1 Gy. SA-β-gal, a marker for endothelial dysfunction, increased 1.2-fold after 0.05 Gy and 1.5-fold after 0.1 Gy. IL-6 and CCL2 increased 2-fold after 0.5 Gy, while SA-β-gal had a 1.5-fold increase. After 2 Gy IL-6 increased 3-fold, CCL2 increased 4-fold and SA-β-gal had a 1.5-fold increase.
Shen et al., 2018	In vivo. Male mice were irradiated with 18 Gy of X-rays. Endpoints were assessed in the aorta.	TNF-α and ICAM-1 increased 2-fold following irradiation. Apoptosis, a marker of endothelial dysfunction, increased 5-fold.
Chang et al., 2017	In vitro. Human endothelial cells were irradiated with 10 Gy of X-rays at a dose rate of 1.5 Gy/min.	IL-8 increased 4-fold following irradiation. IL-1α, IL-6, and TNF-α were also increased but significance was not indicated. Apoptosis increased 5-fold.
Ungvari et al., 2013	In vitro. Primary rat endothelial cells were irradiated with 6 Gy of ¹³⁷Cs gamma rays.	IL-6 secretion increased 1.8-fold, IL-1α increased 1.6-fold, MCP-1 increased 1.4-fold, and IL-1β increased 1.6-fold. SA-β-gal positive cells increased from 0% at control to ~30%.
Ramadan et al., 2020	In vitro. Human endothelial cells were irradiated with either 0.1 or 5 Gy of X-rays at a dose rate of 0.5 Gy/min.	At 5 Gy, MCP-1 increased 4-fold, IL-1β increased 1.5-fold, IL-8 and VCAM-1 increased 2-fold, and IL-6 increased 3-fold. SA-β-gal activity increased by 1.5-fold.

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

Time Concordance

Reference	Experiment Description	Result
Shen et al., 2018	In vivo. Male mice were irradiated with 18 Gy of X-rays. Endpoints were assessed in the aorta.	3 days post irradiation ICAM-1 increased by 1.25-fold and apoptosis increased 3-fold. After 7 days ICAM-1 and TNF-α both reached a peak with a 2-fold increase while apoptosis also reached a peak with a 5-fold increase. Both pro-inflammatory and endothelial dysfunction markers showed a linear decrease from day 14 to 84 post-irradiation.
Ramadan et al., 2020	In vitro. Human endothelial cells were irradiated with 5 Gy of X-rays at a dose rate of 0.5 Gy/min.	Pro-inflammatory mediators were significantly increased as soon as 24 hours post-irradiation. After 7 days MCP-1 increased 4-fold, IL-1β increased 1.5-fold, IL-8 and VCAM-1 increased 2-fold, and IL-6 increased 3-fold. SA-β-gal activity increased by 1.5-fold.

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

Pro-inflammatory mediators can induce endothelial cell senescence and subsequent endothelial dysfunction. Senescent endothelial cells can secrete many pro-inflammatory cytokines and chemokines, contributing to further senescence of other endothelial cells and further endothelial dysfunction (Hughson et al., 2018; Wang et al., 2016).

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

The majority of the evidence is derived from in vitro studies, and a single in vivo study in male pre-adolescent mice.