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Relationship: 2353

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 Increased proinflammatory mediators

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

Increased proinflammatory mediators

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	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 Do not cite	Under Development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

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI

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, induces pain stimulation, and increases 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, Ekdahl doi: 10.1080/14686996.2019.1625721). Activation of the bradykinin system leads to increase of proinflammatory mediators due to increased production of proinflammatory mediator bradykinin(https://doi.org/10.1161/01.CIR.95.5.1115) as well as upregulating bradykinin receptor 1 (BDKRB1) and 2(BDKRB2), leading to induction of proinflammatory mediators such as IL-2, IL-6 and IL-8 (https://doi.org/10.1165/rcmb.2002-0040OC) and the activation of the NFKb pathway leading to production of proinflammatory mediators TNF and IL1(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC507648/).

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

Bradykinin (BK) system activation causes increased production of bradykinin. Bradykinin has been established as a potent proinflammatory mediator due to bradykinin’s role in inflammation. BK acts as a vasodilator, increases vascular permeability, and stimulates prostaglandin synthesis(https://www.ncbi.nlm.nih.gov/books/NBK537187/).

Bradykinin can also induce proinflammatory cytokine production such as TNF, IL2, IL6, and IL8 through stimulation of ERK1/2 and p38 MAPK pathways, causing inflammation and leading to an increase in proinflammatory mediators (https://www.frontiersin.org/articles/10.3389/fphar.2020.01278/full).

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

stressor	species	study type	dose	KE upstream (bradykinin activation)	KE down stream (proinflammatory mediator increase)	description	reference
bradykinin	airway smooth muscle cells	in vivo	1 micro-meter BK for 0 to 24 h		Bradykinin significantly increased IL-6, greater dose of BK, greater IL6 levels . BK-induced IL-6 expression may be regulated by p38 MAPK and ERK1/2 pathways.	Study of airway smooth muscle cells that shows how Bradykinin induces IL6 production. bradykinin -> IL6	Huang et al, 2002. doi: https://doi.org/10.1165/rcmb.2002-0040OC
bradykinin	human lung tissue	in vivo	0, 0.1, 1, 10, 100, and 1000 nM of Bradykinin		IL6 and IL8 production increased as BK dose increased. Use of bradykinin receptor antagonists caused IL6 and IL8 levels to decrease. Phosphorylation of p38 MAPK and ERK1/2 were rapidly induced as a result of BK stimulation.	Study indicating how Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms. Bradykinin -> ERK/p38 MAPK -> IL-6/IL-8	Hayashi et al. 2000. doi: 10.1034/j.1399-3003.2000.016003452.x.
bradykinin	human lung fibroblast cell line WI-38	in vivo	1, 10, 100, 1000 nM of Bradykinin		Bradykinin sharply increases production of proinflammatory cytokine IL1-B and activates transcription factor NFK-B.	Stimulation of human lung fibroblast cell line WI-38 with Bradykinin led to increased levels of proinflammatory cytokines interleukin 1-beta and activation of NFKB. Bradykinin -> IL-1B/NFKB	Pan et al, 1996. doi: 10.1172/JCI119009
						A review of studies establishes how bradykinin plays a prominent role in inflammation as a potent proinflammatory agent. Bradykinin is a vasodilator which widens blood vessels, which allows fluid to leak from the vessel into tissues, increasing inflammation. Bradykinin -> proinflammatory mediator	Hornig et al. 1997. doi: https://doi.org/10.1161/01.CIR.95.5.1115
						A review article establishing bradykinin as a proinflammatory mediator because bradykinin causes increased vasodilation and vascular permeability, leading to the induction of inflammation and inflammatory cytokines Bradykinin -> proinflammatory mediator -> cytokines	Goilas et al. 2007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658795
						Bradykinin-induced B2R signals generate IL-6 and the activation of B1R or B2R can result in Substance P(SP) production with both IL-6 and SP participating in the recruitment of neutrophils and the activation of JAK2 cell signals. Bradykinin -> B2R signalling -> IL-6 -> B1R/B2R -> SP -> neutrophils/JAK2	Curran et al, 2020. https://doi.org/10.3389/fphar.2020.01278
SARS-COV-2	human	in vivo	9 BAL samples of critically ill COVID-19 patients and 40 control	Expression of kininogen and kallikreins expressed in COVID-19 BAL, but not control samples. Bradykinin receptors BKB2R and BKB1R are expressed 207 and 2945 fold higher in COVID-19 samples than the control samples	proinflammatory cytokine IL2 highly upregulated in COVID-19 BAL samples compared to control, IL2 is induced by BK in the lung, causing vascular leakage	Proinflammatory cytokine IL2 was found highly upregulated in symptomatic but not asymptomatic COVID-19 patients and is upregulated (21 fold) in the BAL samples compared to controls. This cytokine is induced by BK in the lung, and causes vascular leakage syndrome (VLS), which appears to be mediated through CD44. Bradykinin -> IL-2 -> CD44 -> vascular leakage syndrome	Garvin et al, 2020. doi: 10.7554/eLife.59177
							https://pubmed.ncbi.nlm.nih.gov/23361105/

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

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
Curran, C. Rivera, D. Kopp, J. Covid-19 usurps host regulatory networks. Frontiers. Pharmacol., 14 August 2020 | https://doi.org/10.3389/fphar.2020.01278
Hayashi R, et al. Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms. Eur Respir J. 2000 Sep;16(3):452-8. doi: 10.1034/j.1399-3003.2000.016003452.
Hornig B., Kohler C., and Drexler H.. Role of Bradykinin in Mediating Vascular Effects of Angiotensin-Converting Enzyme Inhibitors in Humans. Circulation. 4 Mar 1997. Circulation. 1997;95:1115–1118. https://doi.org/10.1161/01.CIR.95.5.111
Huang, C. Tliba, O. Panettieri, R., Amrani, Y. Bradykinin Induces Interleukin-6 Production in Human Airway Smooth Muscle Cells. American Journal of Respiratory Cell and Molecular Biology. 2002. Vol 28, issue 3; doi:https://doi.org/10.1165/rcmb.2002-0040OC
Garvin, M. 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
Golias Ch, Charalabopoulos A, Stagikas D, Charalabopoulos K, Batistatou A. The kinin system--bradykinin: biological effects and clinical implications. Multiple role of the kinin system--bradykinin. Hippokratia. 2007;11(3):124-128.
Pan ZK, Zuraw BL, Lung CC, Prossnitz ER, Browning DD, Ye RD. Bradykinin stimulates NF-kappaB activation and interleukin 1beta gene expression in cultured human fibroblasts. J Clin Invest. 1996;98(9):2042-2049. doi:10.1172/JCI119009
Pirahanchi Y, Sharma S. Physiology, Bradykinin. [Updated 2020 Aug 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537187/