Infection of mice with lactate dehydrogenase—elevating virus destroys the subpopulation of kupffer cells involved in receptor-mediated endocytosis of lactate dehydrogenase and other enzymes

Abstract

In previous experiments in rats, we have shown that the rapid plasma clearance of a number of clinically important enzymes is due to receptor-mediated endocytosis by Kupffer cells and other resident macrophages. Others have shown that infection of mice with lactate dehydrogenase-elevating virus, a virus that proliferates in macrophages, leads to reduced plasma elimination of these enzymes. This paper integrates these two sets of experiments. Plasma elimination of intravenously injected, radioactively labeled lactate dehydrogenase M4 and mitochondrial malate dehydrogenase in mice was shown to be caused in part by uptake in liver, spleen and bone. Uptake of lactate dehydrogenase M4 by these tissues was, to a large extent, saturable and the two dehydrogenases competitively inhibited each other's clearance. These results suggest that, also in mice, these enzymes are partly cleared from plasma by endocytosis by way of a common receptor on cells (probably macrophages) from liver, spleen and bone marrow. Morphometrical data showed that normal mouse liver contains 23 x 10(6) Kupffer cells/cm3. This number was reduced to about 30% of that of controls 24 hr after infection of mice with lactate dehydrogenase-elevating virus but returned to normal within the next 9 days. The saturable component of uptake of lactate dehydrogenase M4 by liver, spleen and bone had disappeared 24 hr after infection with the virus, and did not return after the Kupffer cell population had recovered. Our findings suggest that lactate dehydrogenase M4 is, to a large extent, removed from the circulation by way of a receptor on a subpopulation of macrophages that is permissive for replication of lactate dehydrogenase-elevating virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury

“…This process has been studied in vivo using radiolabeled derivatives of serum enzymes and in vitro using purified KC populations. [7][8][9] Based on these results, it seems likely that modulators of KCs would disrupt normal pathways of serum enzyme clearance.…”

Fatty Acid Binding Protein 7 Regulates Phagocytosis and Cytokine Production in Kupffer Cells during Liver Injury

“…It was shown that KCs infiltrate and phagocytose apoptotic hepatocytes during 6 to 48 hours after CCl 4 administration 20 and that the clearance of liver enzymes by KCs is closely associated with their serum levels after liver injury. 33,34 We demonstrated that there was a decrease in the hepatocyte-enwrapping KCs and in the infiltration of KCs into the necrotic region of Fabp7-KO liver. However, the serum liver enzymes were higher in Fabp7-KO mice during acute liver injury than in WT mice, despite that no significant difference in the extent of necrotic area and the amount of the oxidative stress were detected in Fabp7-KO liver.…”

Removal of lactate dehydrogenase-elevating virus from human-in-mouse breast tumor xenografts by cell-sorting

“…By recognizing a trypsin-sensitive Ia-related receptor (Kowalchyk and Plagemann, 1985), LDV can specifically infect and propagate in a small population of murine macrophages responsible for clearing extracellular lactate dehydrogenase (LDH) (Plagemann et al, 1995; Riley et al, 1960; Ritzi et al, 1982; Smit et al, 1990). Removal of LDV from tumors by traditional approaches, namely through tissue culture in vitro or by rat transplantation, is based on the assumption that mouse macrophages cannot survive under these conditions and thus LDV disappears over time.…”