Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors
Open accessAbstract
Liver fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury. We have studied a model of spontaneous recovery from liver fibrosis to determine the biological mechanisms mediating resolution. Livers were harvested from rats at 0, 3, 7, and 28 d of spontaneous recovery from liver fibrosis induced by 4 wk of twice weekly intraperitoneal injections with CCl4. Hydroxyproline analysis and histology of liver sections indicated that the advanced septal fibrosis observed at time 0 (peak fibrosis) was remodeled over 28 d of recovery to levels close to control (untreated liver). alpha-Smooth muscle actin staining of liver sections demonstrated a 12-fold reduction in the number of activated HSC over the same time period with evidence of HSC apoptosis. Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis. Collagenase activity in liver homogenates increased through recovery. We suggest that apoptosis of activated HSC may vitally contribute to resolution of fibrosis by acting as a mechanism for removing the cell population responsible for both producing fibrotic neomatrix and protecting this matrix from degradation via their production of TIMPs.
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Liver fibrosis can be a reversible process under certain conditions, particularly if the underlying cause of injury is removed.
“One of the most promising developments in the field is the growing consensus that liver fibrosis can be a reversible process under certain conditions, particularly if the underlying cause of injury is removed (84–86).”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [86]
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- Authors
- Iredale, J. P., Benyon, R. C., Pickering, J., McCullen, M., Northrop, M., Pawley, S., Hovell, C., & Arthur, M. J.
- Affiliations
- University of Southampton (GB)
- ORCID
- Iredale, J P
- Venue
- Journal of Clinical Investigation
- Published
- 1998-08-01
- Volume
- 102
- Issue
- 3
- Pages
- 538-549
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508915
- OpenAlex
- W1997064567
- Cited by
- 1,075
- References
- 1
- Citations by year
- 2026: 19 · 2025: 26 · 2024: 29 · 2023: 25 · 2022: 17 · 2021: 32 · 2020: 32 · 2019: 28 · 2018: 36 · 2017: 35 · 2016: 35 · 2015: 43 · 2014: 49 · 2013: 42 · 2012: 55
- FWCI
- 19.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Wessex Medical Research
- British Liver Trust
- Medical Research Council
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- liver fibrosis, hepatic stellate cells, stellate cell apoptosis, metalloproteinase inhibitors, tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, collagenase, carbon tetrachloride-induced fibrosis, extracellular matrix remodeling, alpha-smooth muscle actin
- MeSH terms
- Animals, Carbon Tetrachloride, Gene Expression Regulation, Hydroxyproline, Liver Cirrhosis, Experimental, Male, Procollagen, Remission, Spontaneous, RNA, Messenger, Rats, Sprague-Dawley, Apoptosis, Collagenases, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Matrix Metalloproteinase 1, Rats, Matrix Metalloproteinase 13, Chemical and Drug Induced Liver Injury, Matrix Metalloproteinase Inhibitors
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