Effects of liposome-encapsulated dichloromethylene diphosphonate on macrophage function and endotoxin-induced mortality.
Dichloromethylene diphosphonate (Cl2MDP), encapsulated into liposomes, is known to eliminate splenic and hepatic macrophages. In the present study we investigated the time course of the effects of i.v. injected Cl2MDP-liposomes on macrophage function in rats from 2 h to 14 days postinjection. We further assessed the impact of Cl2MDP-liposomes on endotoxin-induced lethality. Magnetometry was used to measure uptake and distribution of magnetic particles in different organs and to non-invasively monitor cell organelle motion and disappearance of particles in Kupffer cells. Cl2MDP-liposomes administered to rats pre-injected with magnetic particles, resulted in a biphasic impairment of the cell organelle motion after 1 h and 48 h. At 8 h, retained particles started to leave the liver, indicating the begin of an irreversible damage to hepatic macrophages. The released magnetic material was redistributed and taken up primarily by spleen and bone marrow. Pretreatment with Cl2MDP-liposomes for 24 h and 48 h significantly depressed phagocytic capacity for magnetic particles in Kupffer cells. Again, this was compensated by an increased uptake by spleen, lungs, and bone marrow. Interestingly, i.v. administration of endotoxin after pretreatment with Cl2MDP-liposomes resulted in a significant reduction in mortality from 55% to 14%.
Department of Environmental Science and Physiology, Harvard School of Public Health, Boston, MA 02115.
K
K
Tschaikowsky
J D
JD
Brain
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers; D004731:Endotoxins / Q000494:pharmacology*; D005290:Ferric Compounds / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008280:Magnetics; D008297:Male; D010587:Phagocytosis; D051381:Rats; D017207:Rats, Sprague-Dawley
D004337:Drug Carriers; D004731:Endotoxins; D005290:Ferric Compounds; D008081:Liposomes; D004002:Clodronic Acid; C000499:ferric oxide