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Titolo:
Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats
Autore:
Melgert, BN; Olinga, P; Van der Laan, JMS; Weert, B; Cho, J; Schuppan, D; Groothuis, GMM; Meijer, DKF; Poelstra, K;
Indirizzi:
Univ Groningen, GUIDE, Dept Pharmacokinet & Drug Del, NL-9700 AB Groningen, Netherlands Univ Groningen Groningen Netherlands NL-9700 AB B Groningen, Netherlands Univ Erlangen Nurnberg, Dept Med 1, D-91054 Erlangen, Germany Univ Erlangen Nurnberg Erlangen Germany D-91054 -91054 Erlangen, Germany Lab Farmacol & Farmacotherapie Rijksuniv, Groningen, Netherlands Lab Farmacol & Farmacotherapie Rijksuniv Groningen Netherlands herlands
Titolo Testata:
HEPATOLOGY
fascicolo: 4, volume: 34, anno: 2001,
parte:, 1
pagine: 719 - 728
SICI:
0270-9139(200110)34:4<719:TDTKCE>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
HEPATIC STELLATE CELLS; NONPARENCHYMAL CELLS; MANNOSE RECEPTOR; SERUM-ALBUMIN; HEPATOCYTES; EXPRESSION; CARRIER; THERAPY; FIBROGENESIS; DEGRADATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Melgert, BN Ant Deusinglaan 1, NL-9713 AV Groningen, Netherlands Ant Deusinglaan 1 Groningen Netherlands NL-9713 AV therlands
Citazione:
B.N. Melgert et al., "Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats", HEPATOLOGY, 34(4), 2001, pp. 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 (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, becauseDexa(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 IIIdepositions 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 withDexa(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 adual role of this cell type in fibrogenesis of BDL rats.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/06/20 alle ore 09:30:54