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Relationship: 2325

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased extracellular matrix deposition leads to N/A, Liver fibrosis

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased extracellular matrix deposition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

N/A, Liver fibrosis

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of Angiotensin-converting enzyme 2 leading to liver fibrosis	adjacent	Moderate	Not Specified	Young Jun Kim (send email)	Under development: Not open for comment. Do not cite	Under Development
AhR activation leading to liver fibrosis	adjacent	High	High	Xavier COUMOUL (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Fibrosis is the pathological consequence of excessive ECM deposition, primarily composed of collagen type I and III, fibronectin, and glycosaminoglycans. When ECM production exceeds its degradation, tissues undergo progressive stiffening and scarring, leading to functional impairment of affected organs. This process occurs in response to chronic inflammation, mechanical stress, and prolonged injury, where ECM-producing cells (e.g., myofibroblasts, activated stellate cells, fibroblasts) become overactive and produce an excessive matrix. The excessive ECM deposition disrupts normal tissue architecture, interferes with cellular signaling, and promotes further inflammation, hypoxia, and cell death, establishing a self-perpetuating cycle of fibrosis progression (PMID: 24265236).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

- Fibrosis is characterized by a dysregulated balance between ECM synthesis and degradation. Excess ECM, especially cross-linked collagen, alters tissue elasticity, leading to organ dysfunction (PMID: 30213667)
- Studies show that fibrosis is largely irreversible when cross-linked ECM accumulates and inhibits normal tissue remodeling (PMID: 39377183).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

- In vitro studies: Overexpression of collagen in fibroblasts leads to increased matrix stiffness and activation of fibrotic signaling pathways (e.g., TGF-β) (PMID: 39656528)
- Animal models: In CCl₄-induced liver fibrosis models, ECM accumulation precedes histological fibrosis and correlates with elevated hydroxyproline content (PMID: 37941043).
- Clinical data: Patients with liver fibrosis exhibit a progressive increase in collagen deposition (assessed by liver biopsy) that correlates with fibrosis severity (PMID: 35022806).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Reversibility: Early-stage fibrosis may be partially reversible upon ECM degradation, but advanced fibrosis with cross-linked collagen is difficult to resolve.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Collagen deposition can vary among patients with the same CLD and between those with different CLDs at comparable stages of LF (PMID: 35022806).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

ECM overproduction is a hallmark of chronic liver diseases’ progression. Even if specific to the liver, this KER could have been highly relevant for fibrosis in other tissues (lungs, kidneys, heart, and skin).
The relationship has been observed across mammalian species, though the time course of fibrosis development varies.

References

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

Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol. 2013 Oct;3(4):1473-92. doi: 10.1002/cphy.c120035. PMID: 24265236.

Parola M, Pinzani M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019 Feb;65:37-55. doi: 10.1016/j.mam.2018.09.002. Epub 2018 Sep 13. PMID: 30213667.

Pei Z, Fan J, Tang M, Li Y. Ferroptosis: A New Strategy for the Treatment of Fibrotic Diseases. Adv Biol (Weinh). 2024 Oct 8:e2400383. doi: 10.1002/adbi.202400383. Epub ahead of print. PMID: 39377183.

Guan Y, Fang Z, Hu A, Roberts S, Wang M, Ren W, Johansson PK, Heilshorn SC, Enejder A, Peltz G. Live-cell imaging of human liver fibrosis using hepatic micro-organoids. JCI Insight. 2024 Dec 10;10(2):e187099. doi: 10.1172/jci.insight.187099. PMID: 39656528.

Xia S, Huang Y, Zhang Y, Zhang M, Zhao K, Han P, Tian D, Liao J, Liu J. Role of macrophage-to-myofibroblast transition in chronic liver injury and liver fibrosis. Eur J Med Res. 2023 Nov 8;28(1):502. doi: 10.1186/s40001-023-01488-7. PMID: 37941043; PMCID: PMC10631085.

Venkatesh SK, Torbenson MS. Liver fibrosis quantification. Abdom Radiol (NY). 2022 Mar;47(3):1032-1052. doi: 10.1007/s00261-021-03396-y. Epub 2022 Jan 12. PMID: 35022806; PMCID: PMC9538706.