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Relationship: 2357


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
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
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 Do not cite Under Development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).

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


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;

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).

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.

7. Welsh, L. Vascular permeability—the essentials. Upsala Journal of Medical Sciences. Volume 120, 2015-Issue 3. Pages 135-143.

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