Elimination of various subpopulations of macrophages and the development of multiple-organ dysfunction syndrome in mice.
OBJECTIVE
To evaluate the role of specific macrophage subpopulations in the development of zymosan-induced multiple-organ dysfunction syndrome by selective elimination of liver, splenic, alveolar, and peritoneal macrophages.


METHODS
Randomized animal trial.


METHODS
Central animal laboratory at the University Hospital Nijmegen, Nijmegen, the Netherlands.


METHODS
Male C57Bl/6 mice.


METHODS
Elimination of macrophages was accomplished by administration of multilamellar liposomes that contained dichloromethylene bisphosphonate (Cl2MBP). Intravenous, intratracheal, and intraperitoneal administrations induced an elimination of liver and splenic, alveolar, and peritoneal and omental macrophages, respectively. Zymosan (1 mg/g) was injected intraperitoneally at day 0. The liposomes that contained Cl2MBP were administered before and after zymosan challenge. At day 12, all surviving mice were killed.


METHODS
The body weights, temperatures, and mortality rates of the mice were monitored daily. Relative organ weights (ROWs) were calculated from the lungs, liver, spleen, and kidneys after the mice were killed.


RESULTS
The liposomes that contained Cl2MBP, administered intravenously before or after zymosan challenge, did not induce significant changes in the body weight, temperature, or mortality rate. The ROW of the liver was significantly decreased in both treatment groups. Elimination of liver and splenic macrophages after zymosan challenge induced an increased ROW of the lung and a decreased ROW of the liver. The liposomes that contained Cl2MBP, administered intratracheally before zymosan challenge, completely prevented deaths. The body weights, temperatures, and ROWs of the mice were not changed. The liposomes that contained Cl2MBP, administered intraperitoneally, did not change the body weight, temperature, or ROW. The liposomes that contained Cl2MBP, administered intraperitoneally before zymosan challenge, increased the mortality from 50% to 90%.


CONCLUSIONS
These data show that the elimination of specific macrophage subpopulations and the elimination on specific time points in this model had differential effects, indicating a differential role of specific macrophage subpopulations, either protective or detrimental, in the development of multiple-organ dysfunction syndrome.
Nieuwenhuijzen
G A
GA
Department of Surgery, Academic Hospital Nijmegen, The Netherlands.
Knapen
M F
MF
Hendriks
T
T
van Rooijen
N
N
Goris
R J
RJ
D000818:Animals; D004002:Clodronic Acid / Q000008:administration & dosage; D004337:Drug Carriers; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000276:immunology*; D009929:Organ Size; D015054:Zymosan / Q000008:administration & dosage
D004337:Drug Carriers; D008081:Liposomes; D004002:Clodronic Acid; D015054:Zymosan