Studies have shown that Kupffer cell and splenic macrophage, as well as peritoneal macrophage antigen presentation function, was significantly depressed following hemorrhage and remained so for at least 96 hours after resuscitation. Although macrophage antigen presentation was depressed, in all the cell populations studied, it was only the Kupffer cells which were upregulated to produce increased inflammatory cytokines. Furthermore, Kupffer cells from hemorrhaged animals exhibited enhanced, as opposed to reduced toxicity by peritoneal and splenic macrophages. This correlated well with increased cell-associated TNF on Kupffer cells. as well as increased capacity of Kupffer cells to release inflammatory cytokines after hemorrhage. It, therefore, could be postulated that while the enhanced Kupffer cell cytotoxicity may be beneficial in the destruction of pathogens seen in the liver due to bacterial translocation, this same activity may also contribute directly or indirectly to hepatocellular dysfunction and injury which is seen following hemorrhagic shock. Nonetheless, the depression in various immune functions after hemorrhage and resuscitation was comparable in both endotoxin-tolerant and -intolerant mice. Thus, it is debatable whether the alterations in immune function seen after hemorrhage are primarily due to the release of endotoxin into the blood stream during and/or following the hemorrhagic insult. Although translocation and/or endotoxemia occurs following severe hemorrhage, endotoxin may not be the sole or primary agent responsible for the induction of immunodepression after hemorrhage. The depressed Kupffer cell functions and increased inflammatory cytokine release by these cells can be significantly improved by post-treatment of animals with chloroquine, ibuprofen, diltiazem or ATP-MgCl2. Thus, these agents offer new therapeutic modalities in restoring the depressed Kupffer cell immune functions and in the treatment of generalized immunosuppression, as well as for decreasing the susceptibility to sepsis which is observed following severe blood loss.