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Relationship: 2357

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

Bradykinin, activated leads to Hyperinflammation

Upstream event

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

Bradykinin, activated

Downstream event

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

Hyperinflammation

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
Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation	non-adjacent			Penny Nymark (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 Do not cite	Under Development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

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

Bradykinin (BK) plays an important role in the kinin-kallikrein system (KKS) as a regulator of blood pressure and can induce vasodilation, increase blood flow, as well as hypotension. BK is also an important part of the inflammatory process after injury, inducing pain stimulation, and increased vascular permeability (Maas, 10.1007/s12016-016-8540-0). The bradykinin system gets activated through various methods, including nanoparticles and SARS-COV-2 via the contact activation system (Maas, 10.1007/s12016-016-8540-0).

Activation of the bradykinin system increases production of bradykinin. Bradykinin increases vascular permeability and activates endothelial cells(Garvin 2020 doi: 10.7554/eLife.59177). Vascular permeability is present in covid-19 patients with severe vascular damage and neutrophil infiltration (Carvalho 2021 doi: 10.1038/s41577-021-00522-1). Endothelial cell activation by bradykinin causes loss of anti-inflammatory properties and recruitment of proinflammatory mediators such as an increase in IL6, CXCL10, TNF as well as hyperactivation of CD4+ and CD8+, and increased numbers of monocytes, including plasmablast-like neutrophils and eosinophils, all hallmarks of a hyperinflammatory state (Bernard 2020 doi: 10.3390/v13010029). IL-6, activated by bradykinin’s activation of the endothelium, also exacerbates hyperinflammation.

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

Activation of the bradykinin system increases production of bradykinin. Bradykinin increases vascular permeability by DABK binding to B1 receptor, leading to leaky blood vessels (Garvin 2020 doi: 10.7554/eLife.59177), activated RAS and BK which leads to increased permeability of endothelium, (Bernard 2020 doi: 10.3390/v13010029) and bradykinin binding to bradykinin receptor 2 leading to endothelium dysfunction (Zwaveling 2020 doi: 10.1016/j.jaci.2020.08.038). Patients suffering from severe COVID-19 have had evidence of vascular damage, neutrophil infiltration and neutrophil extracellular traps inside micro-vessels (Carvalho 2021 doi: 10.1038/s41577-021-00522-1).

RAAS dysfunction and bradykinin system activation causes Endothelial dysfunction, leading to immunothrombosis and induction of a pro-thrombotic state, causing hyperinflammation and increased platelets (Bernard 2020 doi: 10.3390/v13010029). The endothelial dysfunction also causes loss of anti-inflammatory properties and recruitment of proinflammatory mediators such as an increase in IL6, CXCL10, TNF, hyperactivation of CD4+ and CD8+, and increased numbers of monocytes, including plasmablast-like neutrophils and eosinophils, all hallmarks of a hyperinflammatory state (Ekdahl 2019 doi: 10.1080/14686996.2019.1625721). Bradykinin also activates pathways to proinflammatory cytokine production for cytokines such as IL6, and IL6 exacerbates hyperinflammation (Bernard 2020 doi: 10.3390/v13010029). Finally, bradykinin activation is activated by nanomaterials and specifically coagulation factor XII (F12), and due to the bradykinin system being activated via the contact system, the coagulation cascade is activated as well, leading to increased production of fibrinogen and fibrin, leading to more production of D-dimers, a biomarker for hyperinflammation (Maas, 10.1007/s12016-016-8540-0).

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

description	reference
Review study that details the vascular complications the Bradykinin storm has in covid-19 and discusses bradykinin’s role in inflammation and how bradykinin leads to Vasodilation and increased vascular permeability	McCarthy et al, 2021. https://doi.org/10.1016/j.vph.2020.106826
Review study that discusses how bradykinin causes vascular permeability through BDKRB1 receptor by BK1-8, which also causes neutrophil recruitment, leakage of fluid into the lungs and increased inflammatory cells	Garvin 2020 doi: 10.7554/eLife.59177
A review study that discusses endothelium cell infection by SARS-COV-2. Activated RAAS system and bradykinin system activation leads to endothelial cell dysfunction from increased bradykinin. That endothelial cell dysfunction causes immunothrombosis and induces a pro-thrombotic state, leading to hyperinflammation.	Bernard 2020 doi: 10.3390/v13010029
A review study discussing how pulmonary edema can be caused by bradykinin in SARS-COV-2 and how increase in endothelial cell permeability is caused by bradykinin binding to the Bradykinin 2 receptor	Zwaveling 2020 doi: 10.1016/j.jaci.2020.08.038
A review study of immunological insights of COVID-19 patients. Patients suffering from severe COVID-19 have had evidence of vascular damage, neutrophil infiltration and neutrophil extracellular traps inside micro-vessels	Carvalho 2021 doi: 10.1038/s41577-021-00522-1
A review study of the innate immunity study in humans that discusses how endothelial cell dysfunction causes loss of anti-inflammatory properties and recruitment of proinflammatory mediators,markers of hyperinflammation	Ekdahl 2019 doi: 10.1080/14686996.2019.1625721
A review study of vascular permeability, how it gets caused by bradykinin, and how it can lead to hyperinflammation	Welsh 2015 doi: 10.3109/03009734.2015.1064501
A review study that discusses bradykinin induced vascular complications due to COVID-19 and how bradykinin leads to vascular permeability and vasodilation	McCarthy, https://doi.org/10.1016/j.vph.2020.106826)

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

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

References

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

1. Bernard, I. Limonta, D. Mahal, L. Hobman, T. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2021, 13(1), 29; https://doi.org/10.3390/v13010029

2. Carvalho, T. Krammer, F. Iwasaki, A. The first 12 months of COVID-19: a timeline of immunological insights. Nature Reviews Immunology. volume 21, pages 245–256 (2021). doi: 10.1038/s41577-021-00522-1

3. Ekdahl, K. Fromell, K. Mohlin, C. Teramura, Y. Nilsson, B. A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity. Science and Technology of Advanced Materials. Volume 20, 2019- Issue 1. Page 688-698. doi: 10.1080/14686996.2019.1625721

4. Garvin et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020;9:e59177 DOI: 10.7554/eLife.59177

5. Hofman, Z., de Maat, S., Hack, C.E. et al. Bradykinin: Inflammatory Product of the Coagulation System. Clinic Rev Allerg Immunol 51, 152–161 (2016). https://doi.org/10.1007/s12016-016-8540-0

6. McCarthy, C. Wilczynski, S. Wencesiaum C. Webb, R .A new storm on the horizon in COVID-19: Bradykinin-induced vascular complications. Vascular Pharmacology, 137. https://doi.org/10.1016/j.vph.2020.106826

7. Welsh, L. Vascular permeability—the essentials. Upsala Journal of Medical Sciences. Volume 120, 2015-Issue 3. Pages 135-143. https://doi.org/10.3109/03009734.2015.1064501

8. Zwaveling, S. Wijk, R. Karim, F. Pulmonary edema in COVID-19: Explained by bradykinin? Allergy Clin Immunol. 2020 Dec; 146(6): 1454–1455. DOI:10.1016/j.jaci.2020.08.038