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 α (TNF-α) 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-α 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.