ELIMINATION OF MACROPHAGES BY LIPOSOME-ENCAPSULATED DICHLOROMETHYLENE DIPHOSPHONATE SUPPRESSES THE ENDOTOXIN-INDUCED PRIMING OF KUPFFER CELLS

This study was performed to elucidate the role of Kupffer cells during endotoxemia by assessing the consequences of macrophage depletion by liposome-encapsulated dichloromethylene diphosphonate (L-DMDP) following lipopolysaccharide (LPS) treatment. Results show that more than 90% of the largest Kupffer cells, arbitrarily termed KC3, were eliminated, while only 50% of the smaller Kupffer cells were depleted. The selective elimination of a subpopulation of Kupffer cells was accompanied by a significant attenuation of endotoxin (LPS)-induced serum tumor necrosis factor activity by almost 90%. Hepatic sequestration of neutrophils into the liver after LPS injection was not altered by L-DMDP. The priming action of LPS on superoxide release by neutrophils recovered from the liver in response to in vitro PMA or zymosan was not altered by L-DMDP. However, the LPS-induced priming of superoxide formation in vitro by Kupffer cells, particularly KC3, was significantly attenuated. These results indicate that selective elimination of a subpopulation of Kupffer cells by L-DMDP downregulates the LPS-induced cytokine release in vivo and endotoxin-mediated priming of hepatic macrophages for enhanced formation of toxic oxygen metabolites. However, biological activities of neutrophils (i.e., superoxide release and hepatic sequestration) are not altered by L-DMDP, further emphasizing the specificity of L-DMDP action on Kupffer cells.