Aop: 392

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [AO]”. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Dysregulated fibrinolysis/bradykinin leading to hyperinflammation

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Penny Nymark, Institute of Environmental Medicine, Karolinska Institute, Sweden

Marvin Martens, Maastricht University, Netherlands

Merlin Mei, Environmental Protection Agency, US

Holly Mortensen, Environmental Protection Agency, US

Dan Jacobson, Oak Ridge National Laboratory, US

Jenny Waspe, Sheffield Hospital, UK

Sabina Halappanavar, Health Canada, Canada

CIAO members (https://www.ciao-covid.net/)

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Penny Nymark   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Penny Nymark
  • Merlin Mei
  • Sabina Halappanavar
  • Marvin Martens

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on November 12, 2021 04:14
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Fibrinolysis, decreased October 19, 2021 11:33
Bradykinin system, hyperactivated October 19, 2021 12:35
Increased, secretion of proinflammatory mediators November 29, 2021 13:40
Increased, recruitment of inflammatory cells November 29, 2021 13:54
Hyperinflammation November 19, 2021 06:29
Hypofibrinolysis leads to Bradykinin, activated April 20, 2021 02:45
Hypofibrinolysis leads to Increased proinflammatory mediators October 19, 2021 16:15
Bradykinin, activated leads to Hypofibrinolysis October 19, 2021 15:49
Bradykinin, activated leads to Increased proinflammatory mediators October 19, 2021 16:06
Bradykinin, activated leads to Hyperinflammation October 19, 2021 16:19
Increased proinflammatory mediators leads to Recruitment of inflammatory cells November 26, 2021 12:10
Recruitment of inflammatory cells leads to Hyperinflammation April 20, 2021 02:46
Sars-CoV-2 February 23, 2021 04:50
nanoparticles December 21, 2016 09:40

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

This AOP describes a sequence of molecular, cellular and tissue events associated with immune response, and leading to an uncontrolled, self-perpetuating inflammatory response referred to as hyperinflammation. The AOP is developed with the intent to clarify the complex inflammatory processes associated with the ongoing COVID-19 pandemic caused by the coronavirus SARS-CoV-2. In the broader context, this AOP is applicable to other fields of research including toxicology, with a specific focus on the toxicity and inflammatory elements of nanomaterials. AOP 392 is referred to as a “hub” AOP since it is hypothesized to describe and connect the process of hyperinflammation to other related AOPs, including organ, individual, population, or community-focused AOPs. Such AOPs can include the COVID-19 associated AOPs currently in development (e.g. AOPs 319 and 320) or previously established AOPs (e.g. AOP 173 and 302). In addition, the AOP may be used as a basis for development of new AOPs fit for specific purposes, including e.g. connection to MIEs relevant for SARS-CoV-2 such as the ACE2 binding KE, which leads to the imbalanced fibrinolysis/bradykinin activation MIEs (AOP392).

Fibrinolysis (MIE) is the breakdown of fibrin in blood clots which prevents blood clots from growing too large, and hypo-fibrinolysis occurs when the fibrinolysis process becomes impaired. High levels of the SERPINE1 inhibitor and dysregulation of the uPA/uPAR system found in COVID-19 patients are the main weights of evidence found in support of hypo-fibrinolysis(KE1866). Bradykinin is a peptide that plays an important role in blood pressure regulation and inflammation. Activation of the bradykinin system, causing a bradykinin upregulation, is seen in BAL samples of COVID-19 patients, as well as evidence of B1 and B2 receptor binding in COVID-19 patients(KE1867). Decrease of fibrinolysis and bradykinin upregulation causes inflammation, which evolves into hyperinflammation, an uncontrolled and self-perpetuating inflammatory process that results in tissue damage. Further exploration of how inflammation becomes uncontrolled and evolves into hyperinflammation is needed. There are high serum levels of pro-inflammatory cytokines such as IL-6, CXCL8, and TNF, indicating inflammation (KE1496 and 1497) as well as evidence of high D-dimer, CRP, neutrophil, and a lack of lymphocytes, all evidence of hyperinflammation(AO 1868).

The WoE involving nanomaterials, the other stressor associated with the AOP, is that certain nanomaterials directly interact with coagulation factor XII (FXII). Several proteins of the coagulation system, including fibrinogen and kallikrein, bind to TiO2 and α-Fe2O3 nanoparticles (NPs), and induce clot formation triggered by FXII. This leads to fibrinolysis decrease (KE1866). Nanomaterial activation of FXII also activates the bradykinin system and generates increased bradykinin (KE1867). When proteins of the coagulation system bind to TiO2 and α-Fe2O3 NPs, it causes the release of proinflammatory cytokines, leading to inflammation (KE1496 and 1497), and eventually leading to hyperinflammation (AO1868).

COVID-19 has been a global pandemic that the world has faced for over a year, making this AOP relevant to the understanding of the disease. The other applicability of the AOP is through nanomaterials, including examples such as TiO2, which can promote activation of this AOP in the same mechanism. Nanoparticles such as TiO2 are included in many essential items of day to day life, including food and drug treatments, making this AOP applicable to the future of human health.

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

AOP 392 is developed as a part of the CIAO project, Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway (AOP). The overall goal was to organize, consolidate, and understand the vast amount of data that is constantly evolving as a result of the COVID-19 pandemic and identify knowledge gaps that may be missing using the AOP framework. Many AOPs were developed as a part of the CIAO project, each AOP focusing on a specific element of the SARS-COV-2 virus responses in humans. AOP392 focuses on the inflammatory responses.

AOP 392 covers a set of events that act in concert towards perturbing inflammation. Hypo-fibrinolysis represents the first event (KE1866), in which interaction with SARS-COV-2 or nanomaterials causes decreased fibrinolytic response. The activation of the bradykinin system(KE1867) (MIE2), also instigated by SARS-COV-2 or nanomaterial stressors, can overactivate the bradykinin system and increases bradykinin production. As a result of hypo-fibrinolysis (KE1866), and bradykinin activation (KE1867), there is an increase in pro-inflammatory mediators secretion (KE1496), which signals the recruitment of pro-inflammatory cells into the lungs (KE1497). This KE process represents the changes occurring in inflammation. The increase in pro-inflammatory cells levels lead to a higher neutrophil to lymphocyte ratio, increased CRP, and high D-dimer and ferritin levels, all hallmarks of a hyperinflammatory state (KE1868). Hyperinflammation plays a critical role in driving the severity of the COVID-19 disease. Further exploration of the inflammation to hyperinflammation process is needed.

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 1866 Fibrinolysis, decreased Hypofibrinolysis
2 MIE 1867 Bradykinin system, hyperactivated Bradykinin, activated
3 KE 1496 Increased, secretion of proinflammatory mediators Increased proinflammatory mediators
4 KE 1497 Increased, recruitment of inflammatory cells Recruitment of inflammatory cells
5 AO 1868 Hyperinflammation Hyperinflammation

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, 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). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help
Name Evidence Term
Sars-CoV-2 High
nanoparticles High

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. 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
humans Homo sapiens High NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help