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

Kupffer cells (KC) play an important role in the pathogenesis of inflammato ry liver diseases leading to fibrosis. Anti-inflammatory drugs are only eff ective when administered at high doses that may cause side effects. Therefo re, dexamethasone coupled to mannosylated albumin (Dexa(5)-Man(10)-HSA) was designed by us to selectively deliver this anti-inflammatory drug to the K C. The effectiveness of Dexa(5)-Man(10)-HSA was studied both in organ cultu res and fibrosis induced by bile duct ligation (BDL) in rats. Dexa(5)-Man(1 0)-HSA accumulated in livers of both healthy and fibrotic rats (67% +/- 5% and 70% +/- 9% of the dose, respectively) and uptake was found almost exclu sively in KC. Active dexamethasone was liberated from its carrier, because Dexa(5)-Man(10)-HSA could effectively inhibit nitric oxide (NO) and tumor n ecrosis factor alpha (TNF-alpha) release in endotoxin-activated liver slice s. In vivo, however, this was associated with increased collagen I and III depositions and enhanced tissue inhibitor of metalloproteinase-1 (TIMP-1) m RNA expression. This was accompanied by a decreased influx of reactive oxyg en 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)-HS A treatment also replenished the depleted glycogen stores in hepatocytes of BDL livers. In conclusion, our studies showed selective delivery of dexame thasone to KC with Dexa(5)-Man(10)-HSA. This conjugate reduced intrahepatic ROS in vivo and TNF-alpha production in vitro and prevented glycogen deple tion 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.