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Relationship: 2772

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

Oxidative Stress leads to Increased pro-inflammatory mediators

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

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of energy leads to vascular remodeling adjacent Moderate Moderate Vinita Chauhan (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 High NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female Low
Unspecific Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Juvenile Low
Adult Low
Not Otherwise Specified 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

The increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS) during a state of oxidative stress can stimulate an increase in pro-inflammatory mediators. Reactive oxygen and nitrogen species (RONS) cause cellular damage, which leads to the production of pro-inflammatory mediators (Slezak et al., 2015; Sylvester et al., 2018; Wang et al., 2019a). In addition, ROS can act as second messenger signalling molecules in activating pro-inflammatory transcription factor nuclear factor kappa B (NF-κB), resulting in increased production of pro-inflammatory cytokines and adhesion factors (Ping et al., 2020; Slezak et al., 2017; Slezak et al., 2015; Sylvester et al., 2018; Venkatesulu et al., 2018; Wang et al., 2019a). The inflammatory state induced by RONS will further increase RONS, leading to a cycle of chronic inflammation and oxidative stress (Venkatesulu et al., 2018; Wang et al., 2019a).

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 Supporting this KER

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

Overall weight of evidence: Moderate

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 biological plausibility of the linkage between oxidative stress and pro-inflammatory mediators is strongly supported by review papers on the subject (Ping et al., 2020; Ramadan et al., 2021; Slezak et al., 2017; Slezak et al., 2015; Sylvester et al., 2018; Venkatesulu et al., 2018; Wang et al., 2019a). Pro-inflammatory mediators are released in instances of cell damage to recruit macrophages, monocytes, and other scavengers to ingest and degrade dead and damaged cells. As a major pathway of cell damage, oxidative stress causes upregulation of pro-inflammatory mediators including NF-κB, transforming growth factor-β (TGF-β), tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) (Ping et al., 2020; Slezak et al., 2017; Slezak et al., 2015; Sylvester et al., 2018; Venkatesulu et al., 2018; Wang et al., 2019a). Oxidative stress also stimulates a rise in pro-inflammatory adhesion factors, such as E-selectin, intercellular adhesion molecule-1 (ICAM1), and vascular cell adhesion molecule-1 (VCAM1), which facilitate inflammation by assisting the entrance of inflammatory cells into tissues and recruiting macrophages (Ping et al., 2020; Slezak et al., 2017; Slezak et al., 2015; Sylvester et al., 2018; Venkatesulu et al., 2018; Wang et al., 2019a). 

Once antioxidant levels become exhausted in a state of oxidative stress, ROS are present in higher concentrations and can therefore act more effectively as second messenger signalling molecules in activating pro-inflammatory transcription factors, such as NF-κB, and stimulating production of pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-α (Ping et al., 2020; Sylvester et al., 2018; Wang et al., 2019a). NF-κB is normally kept in an inactive state through formation of a complex with the IkB family of inhibitor proteins but is activated by oxidative stress through nuclear translocation of the complex to the promoter areas of inflammation regulatory genes (Ping et al., 2020; Slezak et al., 2017). The macrophages that are recruited in the resulting inflammatory response can also produce ROS and activate the pro-inflammatory mediator, TGF-β, forming a positive feedback loop (Venkatesulu et al., 2018). Another positive feedback loop is formed by ROS and NF-κB, as ROS activates NF-κB, resulting in the expression of the genes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LPO), which are responsible for ROS production (Ping et al., 2020). In addition, NF-κB is also involved in the production of the pro-inflammatory adhesion factors ICAM and VCAM (Ping et al., 2020; Slezak et al., 2017; Slezak et al., 2015). 

Oxidative stress may also result in oxidation of low-density lipoproteins, allowing the lipoproteins to be ingested by macrophages. This could initiate the atherosclerotic process (plaque build-up in the arteries) and subsequently lead to lipid cells secreting pro-inflammatory cytokines, such as IL-1β and TGF-β (Ramadan et al., 2021; Slezak et al., 2017; Sylvester et al., 2018; Ping et al., 2020; Venkatesulu et al., 2018). 

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
  • Chen et al. (2019) found that levels of the pro-inflammatory mediators, IL-6, IFN-γ, and TNF-α, decreased following 7 and 21 days of microgravity exposure, contrary to the trend generally observed following ionizing radiation exposure (Chen et al., 2019).

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 

Metformin (antidiabetic drug) 

50 mg/kg daily for 2 weeks restored SOD and CAT levels while reducing various pro-inflammatory mediators after irradiation 

Karam et al., 2019 

Drug 

ZnO-NPs (antioxidant properties) 

10 mg/kg daily for 2 weeks attenuated all radiation-induced changes to oxidative stress and pro-inflammatory markers 

Abdel-Magied & Shedid, 2019 

Drug 

FSO (contains antioxidants) 

CAT, SOD, GSh and GPx levels were restored, and reduced pro-inflammatory mediator levels 

Ismail et al., 2016 

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 

Karam et al., 2019 

In vivo. Adult male albino rats underwent whole-body irradiation with 5 Gy of 137Cs gamma rays at a rate of 0.665 cGy/s. Measurements of oxidative stress markers, including levels of the antioxidants SOD and CAT, were taken from the heart tissue of the rats, along with measurements of inflammatory markers, including nuclear factor kappa B (NF-κB), tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6), as well as the pro-inflammatory adhesion factors, E-selectin, ICAM, and VCAM. 

Compared to non-irradiated controls, activity levels of SOD and CAT decreased significantly by 57% and 43%, respectively. This was accompanied by significant increases to inflammatory markers by 96%, 335%, and 292% to NF-κB, TNF-α, and IL-6, respectively. There were also similarly significant increases in the endothelial adhesion molecules, E-selectin, ICAM, and VCAM, by 287%, 234%, and 207%, respectively. 

Wang et al., 2019b 

In vitro. Human umbilical vein endothelial cells (HUVECs) were irradiated with 0.2, 0.5, 1, 2, and 5 Gy of 137Cs gamma rays. ROS levels were measured as a marker for oxidative stress, along with pro-inflammatory cytokines, IL-6 and TNF-α. 

Although ROS levels increased in a dose-dependent fashion from 0.5-5 Gy, they did not change significantly until a ~36% increase at 5 Gy. IL-6 levels significant changed at doses >0.2 Gy. IL-6 levels increased from 0 Gy to 0.2 Gy, decreased from 0.2 Gy to 0.5 Gy, and gradually increased again from 0.5 Gy until a maximum increase of ~50% at 5 Gy. TNF-α levels did not change significantly until 2 Gy. TNF-α levels increased by ~25% at 2 Gy and 5 Gy. 

Philipp et al., 2020 

In vitro. Human TICAE cells were irradiated with 0.25, 0.5, 2, and 10 Gy of 137Cs gamma rays at a rate of 0.4 Gy/min. Levels of the antioxidant, SOD1, were measured along with the inflammatory marker, ICAM1, and pro-inflammatory transcription factor STAT1, at 4 hours, 24 hours, 48 hours, and 1 week post-irradiation to assess oxidative stress and pro-inflammatory mediators, respectively. 

SOD1 levels did not follow a dose-dependent pattern of change at any time point. SOD1 levels had a maximum decrease of 0.5-fold at 2 Gy. ICAM1 levels had maximum increases of 1.4-fold at 10 Gy. The earliest increase in STAT1 occurred after 2 Gy. 

Abdel-Magied & Shedid, 2019 

In vivo. Adult, male, Wistar albino rats underwent whole body irradiation with 8 Gy of 137Cs gamma rays at a rate of 0.4092 Gy/min. The antioxidants SOD, CAT, GSH, and GPx were measured to assess IR-induced oxidative stress. The inflammatory markers ICAM1, TNF-α, IL-18, and CRP were measured to examine subsequent changes in pro-inflammatory mediators.  

Compared to non-irradiated controls, SOD, CAT, GSH, and GPx decreased by 53%, 62%, 56%, and 51%, respectively. Compared to non-irradiated controls, ICAM1, TNF-α, IL-18, and CRP increased by ~138%, ~132%, ~150%, and ~116%, respectively. 

Cho et al., 2017 

In vivo. 10-week-old, male, C57BL/6 mice were irradiated with fractionated doses of 40, 60, and 106.7 Gy of 137Cs gamma rays over the course of 4 weeks. Levels of superoxide anion were measured along with the protein expression of the pro-inflammatory mediators TNF-α and MCP-1. 

ROS levels increased to a maximum of 6.3-fold compared to the control at 4 hours post-irradiation. Protein expression of TNF-α and MCP-1 both had a maximum increase of 18.4-fold and 5.8-fold, respectively, at 8 hours post-irradiation. 

Ismail et al., 2016 

In vivo. Female Wistar rats underwent whole-body irradiation with 7 Gy of 137Cs gamma rays at a rate of 0.456 Gy/min. Levels of the antioxidants SOD, CAT, and GSH-Px were measured following irradiation, along with levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and TGF- β1. 

Following irradiation, the activity of antioxidant enzymes significantly decreased following irradiation (19% for SOD, 33% for CAT, and 19% for GSH-Px). This increase in oxidative stress was accompanied by an increase in pro-inflammatory cytokine levels of 199%, 429%, 142%, and 147% for TNF-α, IL-1β, IL-6, and TGF- β1, respectively. 

Ismail et al., 2015 

In vivo. Female Wistar rats underwent whole-body irradiation with 7 Gy of 137Cs gamma rays at a rate of 0.456 Gy/min. Levels of the antioxidants SOD, CAT, and GSH-Px were measured following irradiation, along with levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and TGF- β1.

Following irradiation, the activity of antioxidant enzymes significantly decreased following irradiation (~19% for SOD, ~34% for CAT, and ~16% for GSH-Px). This increase in oxidative stress was accompanied by an increase in pro-inflammatory cytokine levels of ~257%, ~150%, and ~160% for TNF-α, IL-6, and TGF- β1, respectively. 

Chen et al., 2019 

In vivo. Male Sprague Dawley rats underwent 7 and 21 days of tail suspension to simulate microgravity conditions. Levels of H2O2 were measured to analyze microgravity oxidative stress. Levels of IL-6, IFN-γ, and TNF-α were measured to analyze associated changes to pro-inflammatory mediators. 

After 7 days of simulated microgravity, H2O2 levels increased by ~39-75% compared to the control depending on the region of tissue analyzed. After 21 days of simulated microgravity, expression of IL-6, IFN-γ, and TNF-α decreased by ~32-52%, ~39-40%, and ~24-42%, respectively. 

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 

Philipp et al., 2020 

In vitro. Human TICAE cells were irradiated with 0.25, 0.5, 2, and 10 Gy of 137Cs gamma rays at a rate of 400 mGy/min. Levels of the antioxidant SOD1 were measured along with the inflammatory marker ICAM1 at 4 hours, 24 hours, 48 hours, and 1 week post-irradiation to assess oxidative stress and pro-inflammatory mediators, respectively. 

TICAE cells that were irradiated with 10 Gy showed ~1.2-fold increases in SOD1 levels at 24 and 48 hours, a decrease of ~0.2-fold at 1 week, and no change at 4 hours. ICAM1 levels increased by ~1.2-fold at 4 hours, ~1.15 at 24 hours, ~1.1-fold at 48 hours, and ~1.4-fold at 1 week). 

Cho et al., 2017 

In vivo. Male C57BL/6 mice were irradiated with fractionated doses of 40, 60, and 106.7 Gy of 137Cs gamma rays over the course of 4 weeks. Levels of superoxide anion were measured along with the protein expression of the pro-inflammatory mediators and MCP-1 at 4, 8, and 24 hours post-irradiation. 

ROS levels were significantly increased at 4, 8, and 24 hours. ROS generation was highest at 4 hours post-irradiation (6.3-fold increase compared to control) before decreasing by 59% from 4 hours to 8 hours (2.6-fold increase compared to control) and maintaining the same level at 24 hours (2.6-fold increase compared to control). Protein expression of TNF-α and MCP-1 both increased in a time-dependent manner from 0 hours to 8 hours before a significant reduction from 8 hours to 24 hours. Both pro-inflammatory mediators saw their first significant changes at 8 hours, but only TNF-α experienced another significant increase at 24 hours post-irradiation while MCP-1 did not. 

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
  • Positive feedback loop: oxidative stress upregulates production of pro-inflammatory cytokines, which in turn upregulate ROS production. The macrophages that are recruited in an oxidative stress-induced inflammatory response can also produce ROS and activate the pro-inflammatory mediator, TGF-β (Venkatesulu et al., 2018). Another positive feedback loop is formed by ROS and NF-κB, as ROS activates NF-κB, resulting in expression of the genes, COX-2 and 5-LPO, which are responsible for ROS production (Ping et al., 2020).

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

Most evidence defining the relationship is derived from mice or rat models. A low number of in-vitro human studies were available. Males have been studied more often than females. The age of the models remained unspecified in several studies, while a few studies reported evidence from adult and adolescent models.

References

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

Abdel-Magied, N. and S. M. Shedid (2019), “Impact of zinc oxide nanoparticles on thioredoxin-interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma-irradiated rats”, Environmental Toxicology, Vol. 35, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/tox.22879  

Chen, B. et al. (2019), “The Impacts of Simulated Microgravity on Rat Brain Depended on Durations and Regions”, Biomedical and Environmental Sciences, Vol. 32/7, Elsevier, Amsterdam, https://doi.org/10.3967/bes2019.067  

Cho, H. J. et al. (2017), “Role of NADPH oxidase in radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain”, International Journal of Radiation Biology, Vol. 93/11, Informa, London, https://doi.org/10.1080/09553002.2017.1377360  

Ismail, A. F. M., F.S.M. Moawed and M. A. Mohamed (2015), “Protective mechanism of grape seed oil on carbon tetrachloride-induced brain damage in γ-irradiated rats”, Journal of Photochemistry and Photobiology B: Biology, Vol. 153, Elsevier, Amsterdam, https://doi.org/10.1016/j.jphotobiol.2015.10.005  

Ismail, A. F. M., A. A. M. Salem and M. M. T. Eassawy (2016), “Modulation of gamma-irradiation and carbon tetrachloride induced oxidative stress in the brain of female rats by flaxseed oil”, Journal of Photochemistry and Photobiology B: Biology, Vol. 161, Elsevier, Amsterdam, https://doi.org/10.1016/j.jphotobiol.2016.04.031  

Karam, H. M. and R. R. Radwan (2019), “Metformin modulates cardiac endothelial dysfunction, oxidative stress and inflammation in irradiated rats: A new perspective of an antidiabetic drug”, Clinical and Experimental Pharmacology and Physiology, Vol. 46/12, Wiley-Blackwell, Hoboken, https://doi.org/10.1111/1440-1681.13148  

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, Vol. 98/12. https://doi.org/10.1080/09553002.2022.2110306

Philipp, J. et al. (2020), “Radiation Response of Human Cardiac Endothelial Cells Reveals a Central Role of the cGAS-STING Pathway in the Development of Inflammation”, Proteomes, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/proteomes8040030  

Ping, Z. et al. (2020), “Review Article Oxidative Stress in Radiation-Induced Cardiotoxicity”, Oxidative Medicine and Cellular Longevity, Vol. 2020, Hindawi, London, https://doi.org/10.1155/2020/3579143  

Ramadan, R. et al. (2021), “The role of connexin proteins and their channels in radiation-induced atherosclerosis”, Cellular and molecular life sciences: CMLS, Vol. 78/7, Springer, London, https://doi.org/10.1007/s00018-020-03716-3  

Slezak, J. et al. (2017), “Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury”, Canadian Journal of Physiology and Pharmacology, Vol. 95/10, Canadian Science Publishing, Ottawa, https://doi.org/10.1139/cjpp-2017-0121.  

Slezak, J. et al. (2015), “Mechanisms of cardiac radiation injury and potential preventive approaches”, Canadian Journal of Physiology and Pharmacology, Vol. 93/9, Canadian Science Publishing, Ottawa, https://doi.org/10.1139/CJPP-2015-0006  

Sylvester, C. B. et al. (2018), “Radiation-induced Cardiovascular Disease: Mechanisms and importance of Linear energy Transfer”, Frontiers in Cardiovascular Medicine, Vol. 5, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fcvm.2018.00005  

Venkatesulu, B. P. et al. (2018), “Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms”, JACC: Basic to translational science, Vol. 3/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.jacbts.2018.01.014  

Wang, H. et al. (2019a), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, https://doi.org/10.7150/ijbs.35460  

Wang, H. et al. (2019b), “Gamma Radiation-Induced Disruption of Cellular Junctions in HUVECs Is Mediated through Affecting MAPK/NF-κB Inflammatory Pathways”, Oxidative medicine and cellular longevity, Vol. 2019, Hindawi, London, https://doi.org/10.1155/2019/1486232.