Aop: 319

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

Binding to ACE2 leading to lung fibrosis

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Binding to ACE2 leads to lung fibrosis

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
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Authors

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

Young Jun Kim1, Ian Choi1, Jihun Yang2, Chung Seok2,3 Brigitte Landesmann4, Laure-Alix Clerbaux4  and Penny Nymark5

1Korea Institute of Science and Technology (KIST) Europe, Saarbrücken 66123, Germany, 2 NEXT&BIO, South Korea,  3KU-KIST Graduate School of Converging Science and Technology, South Korea 4 F3 Chemical Safety and Alternative Methods Unit incorporating EURL ECVAM, Directorate F – Health, Consumers and Reference Materials Joint Research Centre, European Commission  5 Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden 

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
Young Jun Kim   (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
  • Young Jun Kim
  • Penny Nymark
  • Brigitte Landesmann
  • Ian Choi
  • Laure-Alix Clerbaux

Status

Provides 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. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for comment. Do not cite Under Development 1.96 Included in OECD Work Plan
This AOP was last modified on July 19, 2022 09:31

Revision dates for related pages

Page Revision Date/Time
Increased Angiotensin II April 04, 2021 08:00
Induced dysregulation of ACE2 March 03, 2022 08:59
Accumulation, Collagen May 04, 2022 12:47
Lung fibrosis December 26, 2017 02:10
Binding of agonist, Angiotensin II receptor type 1 receptor (AT1R) March 30, 2021 12:38
Increased, Reactive oxygen species November 27, 2017 13:15
Increase activation, Nuclear factor kappa B (NF-kB) March 30, 2021 13:17
Increased, secretion of proinflammatory mediators January 25, 2022 15:50
Dysregulation, ACE2 expression and activity December 05, 2021 12:24
ACE2 enzymatic inhibition leads to Increased AngII March 17, 2020 06:17
Increased AngII leads to Binding of agonist, Angiotensin II receptor type 1 receptor (AT1R) March 03, 2022 11:35
Binding of agonist, Angiotensin II receptor type 1 receptor (AT1R) leads to Increased, Reactive oxygen species April 10, 2021 11:45
Increased, Reactive oxygen species leads to Increase activation, Nuclear factor kappa B (NF-kB) April 10, 2021 11:46
Increase activation, Nuclear factor kappa B (NF-kB) leads to Increased proinflammatory mediators March 30, 2021 13:01
Increased proinflammatory mediators leads to Accumulation, Collagen March 30, 2021 12:50
Accumulation, Collagen leads to Lung fibrosis May 15, 2020 18:00
PM 2.5 March 02, 2020 05:42
Streptozocin April 26, 2020 05:50
Losartan April 26, 2020 05:51
DX600 February 11, 2021 10:25
cationic polyamidoamine dendrimer (nanoparticle) February 11, 2021 10:29

Abstract

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

Lung fibrosis has a distinct point in idiopathic pulmonary fibrosis from the renin-angiotensin pathway. this system is reported in many works of literature to share many immune/inflammatory responses to lung damage. When ACE2 activity is inhibited, Ang II is not effectively converted into Ang-(1-7). Because of this, the levels of proinflammatory Ang II are increased and accumulated, while the levels of anti-inflammatory Ang-(1-7) are reduced. Most importantly, the Inhibition of ACE2 was shown to enhance the level of Ang II peptides which is a ligand for type 1 angiotensin receptor (AT1R) and is considered one of the risk factors for lung fibrosis, vasoconstriction, endothelial dysfunction, and cell death. The imbalance of the renin-angiotensin system (RAS) plays a critical role in the fibrogenesis and inflammation damage of many organs. Especially the inhibition of membrane ACE-2 enzymatic activity has shown promising potential in the Molecular initiation event which leads to pulmonary fibrosis. This AOP describes the role of ACE-2 in fibrotic damage of the lung as an adverse outcome through the fibrogenic components, proinflammatory cytokines, and oxygen deficiency.

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

ACE2 is an essential enzyme of blood pressure regulation in the renin-angiotensin system. ACE2 is primarily expressed on type II alveolar epithelial cells within the respiratory system. Angiotensin-converting enzyme (ACE) synthesizes the dominant vasoconstriction, inflammatory and profibrotic angiotensin II (Ang II) through its carboxypeptidase function on the decapeptide angiotensin I. In the meantime, Angiotensin-converting enzyme 2 (ACE2) is an exopeptidase that catalyzes the conversion of angiotensin Il to the conversion of angiotensin 1-7 function as vasodilation, anti-inflammation, and anti-fibrotic.  This AOP describes the dysfunction of membrane ACE2, which results in a high level of angiotensin Ang II synthesized by ACE, which can further lead to pulmonary fibrosis by excessive collagen deposition as the most potent profibrotic factor.

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 1740 Induced dysregulation of ACE2 ACE2 enzymatic inhibition
KE 1854 Dysregulation, ACE2 expression and activity ACE2 dysregulation
KE 1752 Increased Angiotensin II Increased AngII
KE 1851 Binding of agonist, Angiotensin II receptor type 1 receptor (AT1R) Binding of agonist, Angiotensin II receptor type 1 receptor (AT1R)
KE 1115 Increased, Reactive oxygen species Increased, Reactive oxygen species
KE 1172 Increase activation, Nuclear factor kappa B (NF-kB) Increase activation, Nuclear factor kappa B (NF-kB)
KE 68 Accumulation, Collagen Accumulation, Collagen
KE 1496 Increased, secretion of proinflammatory mediators Increased proinflammatory mediators
AO 1276 Lung fibrosis Lung fibrosis

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

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Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Not Otherwise Specified 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
Term Scientific Term Evidence Link
mouse Mus musculus 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)

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

References

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