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

Cited 80 time in Web of Science Cited 82 time in Scopus
Authors
Melgert, Barbro N.; Olinga, Peter; Weert, Betty; Cho, Jae-Jin; Schuppan, Detlef; Groothuis, Geny M. M.; Meijer, Dirk K.F.; Poelstra, Klaas
Issue Date
2001
Publisher
Willey Blackwell
Citation
Hepatology 2001;34:719-728
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 (Dexa5-Man10-HSA) was designed by us to selectively deliver this anti-inflammatory drug to the KC. The effectiveness of Dexa5-Man10-HSA was studied both in organ cultures and fibrosis induced by bile duct ligation (BDL) in rats. Dexa5-Man10-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 Dexa5-Man10-HSA could effectively inhibit nitric oxide (NO) and tumor necrosis factor (TNF-) 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 Dexa5-Man10-HSA as compared with untreated BDL rats. Dexa5-Man10-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 Dexa5-Man10-HSA. This conjugate reduced intrahepatic ROS in vivo and TNF- production in vitro and prevented glycogen depletion in vivo, indicating effective pharmacologic targeting. Dexa5-Man10-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.
ISSN
0270-9139
Language
English
URI
https://hdl.handle.net/10371/68653
DOI
https://doi.org/10.1053/jhep.2001.27805
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College of Dentistry/School of Dentistry (치과대학/치의학대학원)Dept. of Dentistry (치의학과)Journal Papers (저널논문_치의학과)
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