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Event: 1867

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Bradykinin system, hyperactivated

Short name

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Bradykinin, activated

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
increased vascular permeability		increased
vasodilation		increased
vascular inflammation		increased

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Dysregulated fibrinolysis/bradykinin leading to hyperinflammation	MolecularInitiatingEvent	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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI

Life Stages

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Sex Applicability

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Term	Evidence
Male	Not Specified
Female	Not Specified

Key Event Description

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Background

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. Hyperactivation of the BK system is associated with vasodilation and vascular leakage allowing for infiltration of inflammatory cells.

How the KE works

BK is formed by the proteolytic activity of kallikrein on kininogens. Kininogens are expressed by alveolar cells (alveolar type 1.1, 1/2, 2.2., 2.3, and 2.4 cells). Plasma kallikrein (produced by the pancreas) processes high-molecular weight kininogen (HMWK produced by the liver) into BK, and tissue kallikrein processes low-molecular weight kininogen (LMWK produced by the liver) into Lys-BK. BK and Lys-BK are ligands for the bradykinin receptor B2R on endothelial cells, e.g. in the alveolar capillaries. Carboxypeptidases further process BK and Lys-BK into des-Arg9-BK and Lys-des-Arg9-BK respectively, which are ligands for B1R on endothelial cells, and which are up-regulated under proinflammatory conditions.

Another factor of the BK-system is the SERPING1 gene which encodes for the C1-inhibitor. BK can only be produced when the C1-inhibitor is not in effect, allowing the plasma kallikrein to process HMWK into BK.

ACE and ACE2, e.g. present on type II pneumocytes in the alveoli, also play direct roles in the inactivation of the bradykinin system. ACE catalyzes conversion of BK into inactive peptides, while ACE2 inactivates des-Arg9-BK (DABK) and Lys-des-Arg9-BK. Thus, down-regulation of the enzymes leads to activation of the bradykinin system. Furthermore, BK receptor signaling (B1R and B2R) is augmented by the Renin-Angiotensin System (RAS), and increased levels of angiotensin II (AngII) and angiotensin 1-9 (Ang1-9) may indicate activation of the BK system (potentially through resensitization of B2R).

Finally, the coagulation factor XII (F12) is a direct activator of kallikrein, through cleavage of prekallikrein into plasma kallikrein.

Evidence for the KEs perturbation

In COVID-19

In response to SARS-COV-2 infection, BK production increases due to the SERPING1 gene that encodes for the C1-inhibitor being strongly downregulated as a result of infection (10.7554/eLife.59177). Downregulation of ACE2 and upregulation of ACE causes RAS to produce the BK-augmenting peptide Ang1-9 (10.3390/v13010029). The shift of the system towards increased production of BK, increased DABK, and increased B1R/B2R signaling leads to a hyperactive BK system or “storm,” potentially responsible for many COVID-19 symptoms. The BK storm is maintained by several points of inhibition, including suppressed NFkappaB, Vitamin D and its receptor, and the previously mentioned decreased expression of SERPING1. BK overproduction causes blood vessels to burst, leading to the leakage of fluid into the lungs, and hyaluronic acid overproduction causing the lungs to be unable to take in oxygen and expel CO2. This ultimately leads to the severe breathing symptoms of COVID-19 (10.7554/eLife.57555). The BK storm is also known to affect other major organs like the kidneys, cardiac tissue, muscles, and the brain.

In addition, the ACE2 receptor is known to be co-expressed with elements of the kallikrein-kinin (bradykinin) system (10.1038/s41598-020-76488-2).

How It Is Measured or Detected

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Near-patient systems

In human samples (e.g. BAL) the activation of the bradykinin system could potentially be measured on transcriptional level, with focus on activation of KLKB1, KNG1, KLK1 (-15), CPN1, and the BK receptors BDKRB1 and BDKRB2, as well as potential down-regulation of SERPING1. Activation of the RAAS system should also be monitored, specifically on AGT, AGTR1, and AGTR2. Additional indications may be obtained from transcriptional up-regulation of ACE2 (potential result as a compensatory mechanism due to the “high-jacking” by the virus) and down-regulation of ACE (10.7554/eLife.59177).

In vitro systems

Whole human blood model for testing the activation of the kallikrein system (10.1016/j.biomaterials.2015.01.031 , 10.1016/j.nano.2017.12.008 , 10.1080/14686996.2019.1625721 ). The system has initially been applied only to nanomaterials.

Domain of Applicability

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References

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

1. 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

2. Sidarta-Oliveira, D., Jara, C.P., Ferruzzi, A.J. et al. SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells. Sci Rep 10, 19522 (2020). https://doi.org/10.1038/s41598-020-76488-2

3. Bernard et al. 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

4. Veerdonk et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. eLife 2020;9:e57555 DOI: 10.7554/eLife.57555

5. Carvalho 2021 doi: 10.1016/j.peptides.2020.170428

6. Ekdahl 2019 doi: 10.1080/14686996.2019.1625721

7. Long 2015 doi:10.3109/17435390.2015.1088589

8. Atzatzi-Aguilar 2015 10.1186/s12989-015-0094-4