Dexamethasone coupled to albumin is selectively taken up by rat nonparenchymal liver cells and attenuates LPS-induced activation of hepatic cells

Background/Aims: The human serum albumin (HSA) conjugate Dexa(10)-HSA was d esigned to specifically deliver the anti-inflammatory drug dexamethasone (D exa) to nonparenchymal cells (NPC) in the rat liver. NPC play an important role in the pathogenesis of acute and chronic inflammatory liver diseases l ike fibrosis, Targeting Dexa to these cells might reduce its adverse effect s and increase the efficacy. Methods: Tissue and intrahepatic distributions of Dexa(10)-HSA were assesse d in normal and fibrotic rats with I-125-labelled conjugate and by immunohi stochemistry. The effect of the conjugate on lipopolysaccharide (LPS)-induc ed inflammation and cell activation was studied in vitro with precision-cut liver slices and in vivo. Results: Ten minutes after i.v. injection 72+/-13% and 65+/-12% of a tracer dose of Dexa(10)-HSA had been taken up in normal and fibrotic livers, resp ectively. Unconjugated Dexa also accumulated in livers, but cellular distri bution studies revealed an accumulation in parenchymal cells (NPC vs. paren chymal cell (PC) ratio=0.29+/-11, p<0.005) whereas Dexa(10)-HSA accumulated in nonparenchymal cells (NPC/PC ratio=7.9+/-3.1). Both coupled and uncoupl ed Dexa showed effective inhibition of LPS-induced NOx and TNF alpha produc tion in precision-cut liver slices, At low concentrations (0.02 mu M), howe ver, Dexa(10)-HSA was more efficient at inhibiting TNF alpha production tha n uncoupled Dexa, In fibrotic rats Dexa(10)-HSA (3 mg/kg) and an equimolar amount of uncoupled Dexa (0.22 mg/kg) both significantly promoted survival after LPS-induced acute inflammation. Conclusion: Dexa(10)-HSA was at least as effective as uncoupled Dexa at inh ibiting LPS-induced effects, which indicates that HSA-bound Dexa is pharmac ologically active. Coupling Dexa to HSA shifted the accumulation of Dexa fr om the PC to the NPC of livers. Since mediator release from NPC is crucial in the initiation and propagation of the fibrotic process, selective delive ry of Dexa in NPC may improve the efficacy and safety of corticosteroid tre atment of liver fibrosis.