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Grard A. P. Nieuwenhuijzen, MD; Maarten F. C. M. Knapen, MD; Thijs Hendriks, PhD; Nico van Rooijen, PhD; R. Jan A. Goris, MD, PhD

Arch Surg. 1997;132(5):533-539.

Abstract
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.

Arch Surg. 1997;132:533-539

Author Affiliations
From the Department of Surgery, Academic Hospital Nijmegen, Nijmegen, the Netherlands (Drs Nieuwenhuijzen, Knapen, Hendriks, and Goris) and the Department of Cell Biology and Immunology, Vrije Universiteit, Amsterdam, the Netherlands (Dr van Rooijen). Dr Nieuwenhuijzen is now with the Department of Surgery, St Elisabeth Hospital, Tilburg, the Netherlands.

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