Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats
Abstract
Kupffer cells (KC) play an important role in the pathogenesis of inflammatory liver diseases leading to fibrosis. Anti-inflammatory drugs are only effective when administered at high doses that may cause side effects. Therefore, dexamethasone coupled to mannosylated albumin (Dexa(5)-Man(10)-HSA) was designed by us to selectively deliver this anti-inflammatory drug to the KC. The effectiveness of Dexa(5)-Man(10)-HSA was studied both in organ cultures and fibrosis induced by bile duct ligation (BDL) in rats. Dexa(5)-Man(10)-HSA accumulated in livers of both healthy and fibrotic rats (67% +/- 5% and 70% +/- 9% of the dose, respectively) and uptake was found almost exclusively in KC. Active dexamethasone was liberated from its carrier, because Dexa(5)-Man(10)-HSA could effectively inhibit nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) release in endotoxin-activated liver slices. In vivo, however, this was associated with increased collagen I and III depositions and enhanced tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression. This was accompanied by a decreased influx of reactive oxygen species (ROS) producing cells in the livers of BDL animals treated with Dexa(5)-Man(10)-HSA as compared with untreated BDL rats. Dexa(5)-Man(10)-HSA treatment also replenished the depleted glycogen stores in hepatocytes of BDL livers. In conclusion, our studies showed selective delivery of dexamethasone to KC with Dexa(5)-Man(10)-HSA. This conjugate reduced intrahepatic ROS in vivo and TNF-alpha production in vitro and prevented glycogen depletion in vivo, indicating effective pharmacologic targeting. Dexa(5)-Man(10)-HSA, however, also accelerated fibrogenesis, which was paralleled by TIMP-1 mRNA induction. Targeting of dexamethasone to KC provides evidence for a dual role of this cell type in fibrogenesis of BDL rats.
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In rat models, some studies failed to demonstrate comparable anti-fibrotic effects and instead reported increased collagen deposition despite effective suppression of inflammatory signaling.
“However, other studies in rat models failed to demonstrate comparable anti-fibrotic effects and instead reported increased collagen deposition despite effective suppression of inflammatory signaling (161)”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [161]
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- Authors
- Melgert, B. N., Olinga, P., Van Der Laan, J. M. S., Weert, B., Cho, J., Schuppan, D., Groothuis, G. M. M., Meijer, D. K. F., & Poelstra, K.
- Affiliations
- University of Groningen (NL)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Corresponding author
- Melgert, Barbro N.
- Weert, Betty
- Venue
- Hepatology
- Published
- 2001-10
- Volume
- 34
- Issue
- 4
- Pages
- 719-728
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2158299509
- Cited by
- 115
- References
- 52
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 9 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 2 · 2014: 7 · 2013: 8 · 2012: 8
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- Kupffer cells, dexamethasone, targeted drug delivery, liver fibrosis, bile duct ligation, liver inflammation, nitric oxide, TNF-α, reactive oxygen species, TIMP-1, glycogen depletion, hepatocytes, collagen deposition
- MeSH terms
- Animals, Collagen, Dexamethasone, Hepatitis, Kupffer Cells, Liver Cirrhosis, Experimental, Liver Glycogen, Male, Nitric Oxide, Serum Albumin, Tumor Necrosis Factor-alpha, Interleukin-10, Rats, Wistar, Tissue Inhibitor of Metalloproteinase-1, Rats
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