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 syndr ome by selective elimination of liver, splenic, alveolar, and peritone al macrophages. Design: Randomized animal trial. getting: Central anim al laboratory at the University Hospital Nijmegen, Nijmegen, the Nethe rlands. Animals: Male C57Bl/6 mice. Interventions: Elimination of macr ophages was accomplished by administration of multilamellar lipo somes that contained dichloromethylene bisphosphonate (Cl2MBP). Intravenous , intratracheal, and intraperitoneal administrations induced an elimin ation of liver and splenic, alveolar, and peritoneal and omental macro phages, 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 kille d. Main Outcome Measures: The body weights, temperatures, and mortalit y 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, admin istered intravenously before or after zymosan challenge, did not induc e significant changes in the body weight, temperature, or mortality ra te. The ROW of the liver was significantly decreased in both treatment groups. Elimination of liver and splenic macrophages after zymosan ch allenge induced an increased ROW of the lung and a decreased ROW of th e liver. The liposomes that contained Cl2MBP, administered intratrache ally before zymosan challenge, completely prevented deaths. The body w eights, temperatures, and ROWs of the mice were not changed. The lipos omes that contained Cl2MBP, administered intraperitoneally, did not ch ange the body weight, temperature, or ROW. The liposomes that containe d Cl2MBP, administered intraperitoneally before zymosan challenge, inc reased the mortality from 50% to 90%.Conclusions: These data show that the elimination of specific macrophage subpopulations and the elimina tion on specific time points in this model had differential effects, i ndicating a differential role of specific macrophage subpopulations, e ither protective or detrimental, in the development of multiple-organ dysfunction syndrome.