Aop: 392

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the 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
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Dysregulated fibrinolysis/bradykinin leading to hyperinflammation

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the 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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Penny Nymark   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Penny Nymark
  • Merlin Mei
  • Sabina Halappanavar
  • Marvin Martens

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.96 Included in OECD Work Plan
This AOP was last modified on August 29, 2022 08:23

Revision dates for related pages

Page Revision Date/Time
Fibrinolysis, decreased October 19, 2021 11:33
Bradykinin system, hyperactivated January 24, 2022 11:39
Increased, secretion of proinflammatory mediators January 25, 2022 15:50
Increased, recruitment of inflammatory cells January 25, 2022 15:52
Hyperinflammation December 29, 2021 02:29
Hypofibrinolysis leads to Bradykinin, activated April 20, 2021 02:45
Hypofibrinolysis leads to Increased proinflammatory mediators January 19, 2022 16:46
Bradykinin, activated leads to Hypofibrinolysis January 24, 2022 11:49
Bradykinin, activated leads to Increased proinflammatory mediators January 14, 2022 15:02
Bradykinin, activated leads to Hyperinflammation October 19, 2021 16:19
Increased proinflammatory mediators leads to Recruitment of inflammatory cells December 07, 2021 10:28
Recruitment of inflammatory cells leads to Hyperinflammation February 08, 2022 14:52
Sars-CoV-2 September 09, 2022 05:09
nanoparticles December 21, 2016 09:40
nanomaterials April 22, 2021 09:28
Titanium dioxide nanoparticles August 29, 2022 08:22
Iron nanoparticles August 29, 2022 08:23

Abstract

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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.

AOP Development Strategy

Context

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. 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.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1866 Fibrinolysis, decreased Hypofibrinolysis
MIE 1867 Bradykinin system, hyperactivated Bradykinin, activated
KE 1496 Increased, secretion of proinflammatory mediators Increased proinflammatory mediators
KE 1497 Increased, recruitment of inflammatory cells Recruitment of inflammatory cells
AO 1868 Hyperinflammation Hyperinflammation

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Prototypical Stressors

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Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

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Term Scientific Term Evidence Link
humans Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

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. More help

Evidence Assessment

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Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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