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Relationship: 2325
Title
Increased extracellular matrix deposition leads to N/A, Liver fibrosis
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite | Under Development |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 Do not cite |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
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
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
Evidence Supporting this KER
Biological Plausibility
-
- 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
-
- 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
- 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
Quantitative Understanding of the Linkage
- 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
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- 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
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.