Macrophage elimination increases bacterial translocation and gut-origin septicemia but attenuates symptoms and mortality rate in a model of systemic inflammation.

Abstract

The central question tested in this study was whether dichloromethylene-diphosphonate (CL2MDP) liposome-mediated elimination of hepatic and splenic macrophages would influence zymosan-induced bacterial translocation and the zymosan-induced generalized inflammatory response. Both an uncontrolled activation of macrophages and the loss of intestinal barrier function have been implicated in the development of adult respiratory distress syndrome and multiple organ failure. Macrophage elimination was accomplished by intravenous injection of 200 microL of CL2MDP-liposome suspension. Control mice received an intravenous injection of 200 microL of phosphate-buffered saline. Two days later, the animals were challenged intraperitoneally with zymosan suspended in paraffin to determine a dose-response curve (0.1, 0.5, or 1.0 mg/g body weight). Twenty-four hours after zymosan challenge, signs of systemic stress were determined, and bacterial translocation to the mesenteric lymph node, liver, spleen, and blood was measured. A separate mortality study was performed with a dose of 1.0 mg/g of zymosan suspension. The incidence of the systemic spread of bacteria was significantly increased in the macrophage-depleted mice. Although systemic bacterial translocation was promoted by macrophage elimination, the systemic toxic response was significantly decreased in all macrophage-depleted groups (p < or = 0.01). The 12-day mortality rate was 0% in the macrophage-depleted groups and 27% in the control group (p = 0.05). The lethal and toxic effects of zymosan appear to be related more to the excessive activation of macrophages than to the systemic spread of bacteria.