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AOP: 377


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

Dysregulated prolonged Toll Like Receptor 9 (TLR9) activation leading to Multi Organ Failure involving Acute Respiratory Distress Syndrome (ARDS)

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
TLR9 activation leading to Multi Organ Failure and ARDS
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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
Gillina Bezemer   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Gillina Bezemer


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page Revision Date/Time
Prolonged TLR9 activation March 26, 2021 06:53
Multi Organ Failure involving Acute Respiratory Distress Syndrome November 19, 2021 05:40
systemic inflammatory response syndrome March 19, 2021 09:50
Toll Like Receptor (TLR) Dysregulation November 23, 2021 16:54
Increased Mortality July 08, 2022 07:32
increased MyD88 activation July 08, 2021 06:04
NLRP3 inflammasome activity, increased June 25, 2021 08:29
Increased, Oxidative Stress February 03, 2022 14:20
Oxidative Stress March 08, 2024 12:28
Diminished protective oxidative stress response October 30, 2023 03:36
Propagation, Oxidative stress September 16, 2017 10:14
Th17 cell migration and inflammation induction November 23, 2020 06:59
Cell injury/death July 15, 2022 09:46
Increase, Cell death March 22, 2023 11:07
increased release of danger/damage associated molecular patterns July 08, 2021 07:14
Platelet-neutrophil interactions, Increased April 08, 2021 08:49
Increased Pro-inflammatory mediators March 21, 2023 15:50
Increased, secretion of proinflammatory mediators May 17, 2023 15:18
formation of neutrophil extracellular traps (NETs) July 08, 2021 07:29
Hyperinflammation December 29, 2021 02:29
Release, Cytokine September 16, 2017 10:14
Increase, Tissue/organ damage November 02, 2020 05:49
Increase, the risk of acute respiratory failure March 10, 2020 02:05
Heart failure June 19, 2018 14:04
Increased, Kidney Failure January 16, 2019 08:57
Occurrence, Kidney toxicity March 04, 2022 10:58
Increased activation, Nuclear factor kappa B (NF-kB) August 27, 2023 03:08
Inflammation, Liver September 16, 2017 10:16
increased platelet surface TLR9 expression July 08, 2021 09:22
Increased, recruitment of inflammatory cells May 12, 2023 17:03
Mitochondrial dysfunction April 17, 2024 08:26
Thrombosis and Disseminated Intravascular Coagulation November 25, 2022 01:38
TLR9 activation leads to MyD88 activation July 08, 2021 10:43
TLR9 activation leads to inflammasome activity, increased July 08, 2021 10:54
MyD88 activation leads to Increased activation, Nuclear factor kappa B (NF-kB) July 08, 2021 10:44
Increased activation, Nuclear factor kappa B (NF-kB) leads to Release, Cytokine July 08, 2021 10:48
Increased activation, Nuclear factor kappa B (NF-kB) leads to Increased pro-inflammatory mediators July 08, 2021 10:50
Increased activation, Nuclear factor kappa B (NF-kB) leads to Increased proinflammatory mediators March 30, 2021 13:01
Release, Cytokine leads to Recruitment of inflammatory cells July 03, 2019 11:52
cell free mitochondrial DNA (mtDNA) March 29, 2021 07:07
unmethylated CpG motifs (DNA;RNA;ODN) March 29, 2021 06:15
SARS-CoV March 01, 2020 10:42
Sars-CoV-2 September 09, 2022 05:09
Danger Associated Molecular Patters (DAMPs) March 26, 2021 04:13
Pathogen Associated Molecular Patterns (PAMPs) March 26, 2021 04:14


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

AOP Development Strategy


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


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

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


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 1842 Prolonged TLR9 activation TLR9 activation
KE 1897 increased MyD88 activation MyD88 activation
KE 1895 NLRP3 inflammasome activity, increased inflammasome activity, increased
KE 1172 Increased activation, Nuclear factor kappa B (NF-kB) Increased activation, Nuclear factor kappa B (NF-kB)
KE 87 Release, Cytokine Release, Cytokine
KE 1493 Increased Pro-inflammatory mediators Increased pro-inflammatory mediators
KE 1497 Increased, recruitment of inflammatory cells Recruitment of inflammatory cells
KE 1708 Th17 cell migration and inflammation induction Th17 cell migration and inflammation induction
KE 1088 Increased, Oxidative Stress Increased, Oxidative Stress
KE 1392 Oxidative Stress Oxidative Stress
KE 1869 Diminished protective oxidative stress response Diminished Protective Response to ROS
KE 211 Propagation, Oxidative stress Propagation, Oxidative stress
KE 177 Mitochondrial dysfunction Mitochondrial dysfunction
KE 55 Cell injury/death Cell injury/death
KE 1825 Increase, Cell death Increase, Cell death
KE 1809 Increase, Tissue/organ damage Increase, Tissue/organ damage
KE 1898 increased release of danger/damage associated molecular patterns increased release of DAMPS
KE 1848 Toll Like Receptor (TLR) Dysregulation TLR Activation/Dysregulation
KE 1900 increased platelet surface TLR9 expression increased platelet tlr9 expression
KE 1899 formation of neutrophil extracellular traps (NETs) NETosis
KE 1857 Platelet-neutrophil interactions, Increased Platelet-neutrophil interactions, Increased
KE 1846 Thrombosis and Disseminated Intravascular Coagulation Thrombosis and DIC
KE 1496 Increased, secretion of proinflammatory mediators Increased proinflammatory mediators
KE 1868 Hyperinflammation Hyperinflammation
KE 902 Inflammation, Liver Inflammation, Liver
KE 1844 systemic inflammatory response syndrome SIRS
KE 1748 Increase, the risk of acute respiratory failure Increase, the risk of acute respiratory failure
KE 1535 Heart failure Heart failure
KE 814 Occurrence, Kidney toxicity Occurrence, Kidney toxicity
KE 759 Increased, Kidney Failure Increased, Kidney Failure

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes 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. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (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

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Old Age Moderate
Adult, reproductively mature Not Specified
Birth to < 1 month Moderate

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. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess 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. More help


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