Pharmacological inhibition of integrin αvβ3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis #
Open accessAbstract
The vitronectin receptor integrin αvβ3 promotes angiogenesis by mediating migration and proliferation of endothelial cells, but also drives fibrogenic activation of hepatic stellate cells (HSCs) in vitro. Expecting antifibrotic synergism, we studied the effect of αvβ3 inhibition in two in vivo models of liver fibrogenesis. Liver fibrosis was induced in rats by way of bile duct ligation (BDL) for 6 weeks or thioacetamide (TAA) injections for 12 weeks. A specific αvβ3 (αvβ5) inhibitor (Cilengitide) was given intraperitoneally twice daily at 15 mg/kg during BDL or after TAA administration. Liver collagen was determined as hydroxyproline, and gene expression was quantified by way of quantitative polymerase chain reaction. Liver angiogenesis, macrophage infiltration, and hypoxia were assessed by way of CD31, CD68 and hypoxia-inducible factor-1α immunostaining. Cilengitide decreased overall vessel formation. This was significant in portal areas of BDL and septal areas of TAA fibrotic rats and was associated with a significant increase of liver collagen by 31% (BDL) and 27% (TAA), and up-regulation of profibrogenic genes and matrix metalloproteinase-13. Treatment increased gamma glutamyl transpeptidase in both models, while other serum markers remained unchanged. αvβ3 inhibition resulted in mild liver hypoxia, as evidenced by up-regulation of hypoxia-inducible genes. Liver infiltration by macrophages/Kupffer cells was not affected, although increases in tumor necrosis factor α, interleukin-18, and cyclooxygenase-2 messenger RNA indicated modest macrophage activation. Conclusion: Specific inhibition of integrin αvβ3 (αvβ5) in vivo decreased angiogenesis but worsened biliary (BDL) and septal (TAA) fibrosis, despite its antifibrogenic effect on HSCs in vitro. Angiogenesis inhibitors should be used with caution in patients with hepatic fibrosis. (Hepatology 2009.)
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Integrins avb3 and avb5 contribute to limiting fibrosis and inhibiting pro-inflammatory cytokine production in bile duct ligation and thioacetamide-induced fibrosis models.
“Other non-TAM receptors, such as integrins avb3 and avb5, have also been shown to contribute to limiting fibrosis and the inhibition of pro-inflammatory cytokine production in the chronic liver disease models of bile duct ligation and thioacetamide-induced fibrosis (45).”
From Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis (2024) · cites this paper as [45]
In liver fibrosis models (TAA- or BDL-induced), Cilengitide unexpectedly exacerbated fibrotic progression, as evidenced by increased collagen septa thickness and upregulation of profibrotic genes TGF-b1 and TIMP-1/2.
“In liver fibrosis models (e.g., TAA-or BDL-induced), Cilengitide unexpectedly exacerbated fibrotic progression, as evidenced by increased collagen septa thickness, upregulation of profibrotic genes TGF-b1 and TIMP-1/2 (165).”
From The mechanotransduction-immune axis in organ fibrosis: dual regulatory mechanisms and translational therapeutic perspectives (2025) · cites this paper as [165]
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- Authors
- Patsenker, E., Popov, Y., Stickel, F., Schneider, V., Ledermann, M., Sägesser, H., Niedobitek, G., Goodman, S. L., & Schuppan, D.
- Affiliations
- University of Bern (CH)
- Beth Israel Deaconess Medical Center (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Merck KGaA, Darmstadt (Germany) (DE)
- Corresponding author
- Schuppan, Detlef
- Venue
- Hepatology
- Published
- 2009-11
- Volume
- 50
- Issue
- 5
- Pages
- 1501-1511
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2779730
- OpenAlex
- W1982854019
- Cited by
- 174
- References
- 56
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 12 · 2022: 4 · 2021: 14 · 2020: 12 · 2019: 12 · 2018: 13 · 2017: 11 · 2016: 15 · 2015: 13 · 2014: 9 · 2013: 12 · 2012: 8
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Funders
- University of Bern
- Deutsche Forschungsgemeinschaft (/14-1)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (122114)
- National Institutes of Health (GRK-750)
- National Institute of Allergy and Infectious Diseases (U19AI066313)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- integrin αvβ3, cilengitide, liver fibrosis, hepatic angiogenesis, hepatic stellate cells, bile duct ligation, thioacetamide, liver hypoxia, macrophage infiltration, Kupffer cells, matrix metalloproteinase-13, collagen deposition, antifibrotic therapy
- MeSH terms
- CD68 Molecule, Animals, Cell Movement, Disease Models, Animal, Endothelium, Vascular, gamma-Glutamyltransferase, Ligation, Liver, Liver Cirrhosis, Male, Snake Venoms, Thioacetamide, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Rats, Wistar, Neovascularization, Physiologic, Platelet Endothelial Cell Adhesion Molecule-1, Integrin alphaVbeta3, Cell Proliferation, Rats, Hypoxia-Inducible Factor 1, alpha Subunit, Hepatic Stellate Cells
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