Coordinate expression of macrophage procoagulant and fibrinolytic activity <i>in vitro</i> and in vivo.

Abstract

Abstract In this study we have utilized endotoxin-responsive (C3H/HeN) and -unresponsive (C3H/HeJ) mouse strains to analyze the effect of endotoxin on inflammatory processes containing stimulated macrophages. An ascitic fluid exudate, rich in macrophages, was induced by i.p. inoculation of thioglycollate broth. In endotoxin-sensitive C3H/HeN mice, subsequent i.p. endotoxin, 250 to 1000 ng, caused a dramatic fall in recoverable macrophages and an influx of neutrophils. Heparin, 20 to 40 U, blocked the disappearance of macrophages but not the influx of neutrophils. Ascitic fluid from thioglycollate broth-injected C3H/HeN mice had fibrinolytic activity, but the fluid became strongly anti-fibrinolytic after i.p. endotoxin injection. In endotoxin-resistant C3H/HeJ mice, subsequent i.p. endotoxin did not induce macrophage disappearance, neutrophil accumulation, or ascitic fluid anti-fibrinolytic activity. Similar findings occurred with peptone or bacillus Calmette Guérin-mediated inflammatory processes in the two strains of C3H mice. In vitro, endotoxin, 1 to 100 ng/ml, increased the expression of pro-coagulant activity and suppressed secretion of plasminogen activator by C3H/HeN macrophages, but had no effect on macrophages from C3H/HeJ mice. The results indicate that stimulated macrophages can initiate pro-coagulant, fibrinolytic, and anti-fibrinolytic pathways. These activities are coordinately regulated as a function of environmental signals. The ratio of fibrinolytic to pro-coagulant activity in the cells' microenvironment appears to closely correlate with the mobility and localization of macrophages in vivo. In addition, the data provide further evidence that the phlogistic effects of endotoxin, at least in low concentrations, are dependent on cell-derived inflammatory mediators.