title: 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.
authors.affiliation: Groningen University Institute for Drug Exploration (GUIDE), Department of Pharmacokinetics and Drug Delivery, University of Groningen, Groningen, The Netherlands. B.Melgert@farm.rug.nl
authors.forename: B N
authors.initials: BN
authors.lastname: Melgert
authors.forename: P
authors.initials: P
authors.lastname: Olinga
authors.forename: J M
authors.initials: JM
authors.lastname: Van Der Laan
authors.forename: B
authors.initials: B
authors.lastname: Weert
authors.forename: J
authors.initials: J
authors.lastname: Cho
authors.forename: D
authors.initials: D
authors.lastname: Schuppan
authors.forename: G M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
authors.forename: K
authors.initials: K
authors.lastname: Poelstra
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage* / Q000378:metabolism; D006505:Hepatitis / Q000188:drug therapy*; D016753:Interleukin-10 / Q000096:biosynthesis; D007728:Kupffer Cells / Q000187:drug effects*; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000008:administration & dosage; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D008112:Liver Glycogen; D012709:Serum Albumin; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D003907:Dexamethasone; D003094:Collagen