Mannose-conjugated alendronate selectively depletes Kupffer cells and inhibits endotoxemic shock in the mice

To elucidate the roles of Kupffer cells in the host-defense mechanisms and liver injury, we synthesized a mannose-conjugated alendronate (MANA) and examined its effects on Kupffer cells and lipopolysaccharide (LPS)-induced liver injury in the mice. Intravenous administration of a small amount of MANA (50 mu mol/kg) rapidly and selectively depleted Kupffer cells in the mice. The depletion of Kupffer cells by MANA resulted in a marked decrease of the production of both TNF-alpha and IL-I beta in the plasma during the liver injury induced by low (1 mg/kg) and lethal (75 mg/kg) doses of LPS. The effect was so remarkable that all animals treated with a lethal dose of LPS survived without any sign of endotoxemia. These findings indicate that Kupffer cells play critical roles in the development of endotoxemia, and that MANA will be useful in studies to elucidate pathophysiological roles of Kupffer cells in various liver diseases. (c) 2006 Elsevier Ireland Ltd. All rights reserved.