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Cited by 115Liver physiology and pathologyNanoparticle-Based Drug DeliveryLiver Diseases and Immunity

The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.

Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

Melgert, Barbro N., Olinga, Peter, Van Der Laan, Judith M.S., Weert, Betty, Cho, Jaejin, Schuppan, Detlef, Groothuis, Geny M. M., Meijer, Dirk K.F., Poelstra, Klaas·2001·Hepatology
DOI 10.1053/jhep.2001.27805
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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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Metadata

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
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2001-10
Volume
34
Issue
4
Pages
719-728
ISSN
0270-9139 (ISSN-L)
DOI
10.1053/jhep.2001.27805
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
Licence
doi.wiley.com/10.1002/tdm_license_1 (tdm, 5083 d)
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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