EFFECT OF CL 184,005, A PLATELET-ACTIVATING-FACTOR ANTAGONIST IN A MURINE MODEL OF STAPHYLOCOCCUS-AUREUS INDUCED GRAM-POSITIVE SEPSIS

Experiments using a murine model of heat-killed Staphylococcus aureus- induced gram-positive bacterial sepsis indicate that the lethal bacter ial effects can be prevented if mice are pretreated with CL 184,005, a platelet-activating factor (PAF) antagonist. CL 184,005 was ineffecti ve when administered after bacterial challenge. Plasma of mice pretrea ted with CL 184,005 contained significantly less tumor necrosis factor (TNF), suggesting that CL 184,005 interferes with TNF synthesis induc ed by S. aureus. Spleen-associated TNF protein was also decreased by p retreatment with CL 184,005. Although TNF levels were significantly de creased in mice treated with CL 184,005, interleukin-6 levels in serum were significantly increased. Athymic mice were also susceptible to t he lethal effects of S. aureus, suggesting that T cells were not invol ved. When rats rendered hypotensive with S. aureus were treated with C L 184,005, their blood pressure was normalized. Mice treated with ente rotoxin B were not protected if they were pretreated with CL 184,005; however, TNF levels in these mice were significantly lower, suggesting that mediators other than PAF and TNF may contribute to the lethal ef fects of enterotoxin.