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Event: 1867

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Bradykinin system, hyperactivated

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Bradykinin, activated

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Human Not Specified

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Male Not Specified
Female Not Specified

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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 (FXII) 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 ACE and upregulation of ACE2 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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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 B1R and B2R, 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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

SARS-CoV-2

Directly, the BK precursor kininogen as well as several kallikreins are up-regulated in COVID-19 patient bronchial alveolar lavage (BAL) samples.

Indirectly, SARS-COV-2 affects the Renin-angiotensin system by downregulating ACE2. With ACE2 unable to  inactivates DABK and Lys-des-Arg9-BK enzymes, an activation of the bradykinin system would be triggered. SARS-COV-2 also highly downregulates the SERPING1 gene, which encodes for the C1-inhibitor, leading to increased bradykinin production.

Nanomaterials

AG, TiO2, and Fe2O3 nanoparticles directly interact with FXII and activate the bradykinin system.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). 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