ELIMINATION OF MACROPHAGES BY LIPOSOME-ENCAPSULATED DICHLOROMETHYLENEDIPHOSPHONATE 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) followi ng 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 selec tive elimination of a subpopulation of Kupffer cells was accompanied b y a significant attenuation of endotoxin (LPS)-induced serum tumor nec rosis factor activity by almost 90%. Hepatic sequestration of neutroph ils into the liver after LPS injection was not altered by L-DMDP. The priming action of LPS on superoxide release by neutrophils recovered f rom the liver in response to in vitro PMA or zymosan was not altered b y 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 rel ease in vivo and endotoxin-mediated priming of hepatic macrophages for enhanced formation of toxic oxygen metabolites. However, biological a ctivities of neutrophils (i.e., superoxide release and hepatic sequest ration) are not altered by L-DMDP, further emphasizing the specificity of L-DMDP action on Kupffer cells.