Elimination of various subpopulations of macrophages and the development of multiple-organ dysfunction syndrome in mice
G. A. Nieuwenhuijzen, M. F. Knapen, T. Hendriks, N. van Rooijen and R. J. Goris
Department of Surgery, Academic Hospital Nijmegen, The Netherlands.
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. DESIGN: Randomized animal trial. SETTING: Central animal
laboratory at the University Hospital Nijmegen, Nijmegen, the Netherlands.
ANIMALS: Male C57Bl/6 mice. INTERVENTIONS: 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. MAIN OUTCOME MEASURES: 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.
