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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 down‐regulates 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. J. Leukoc. Biol. 55: 321–327; 1994.