PROTECTION OF MICE FROM MORTALITY CAUSED BY LIVING AND HEAT-KILLED BACTERIA BY SDZ-MRL-953

Protective effects of SDZ MRL 953, a monosaccharidic lipid A analog wi h a reduced toxicity, were investigated in models of experimental sept ic shock caused by injections of LPS, and inoculations of heat-killed or live bacteria. Female B(6)D()2F(1) mice were challenged with a com bination of galactosamine (800 mg/kg) plus various doses of heat-kille d isolates of Escherichia coli, Pseudomonas aeruginosa, Salmonella typ himurium, and Staphylococcus aureus or LPS from Salmonella abortus equ i. In some experiments, isolates of living bacteria at sublethal inocu la were also combined with galactosamine. More than 90% of the animals died within 24 hr when the challenge was performed either simultaneou sly with or up to 4 hr after an intraperitoneal administration of gala ctosamine. No death was observed when galactosamine was omitted or adm inistered after the microbial or LPS challenge. Pretreatment of the an imals with SDZ MRL 953 (1-10 mg/kg) rendered the animals resistant to the lethal effects of both bacterial and LPS challenge in a time- and dose-dependent manner. The levels of TNF-alpha in control mice rose to greater than 600 pg/ml 2 hr postbacterial or LPS challenge, but were below detection in animals pretreated with SDZ MRL 953. Protection aga inst both the infection and the toxicity of heat-killed bacteria or LP S was also achieved when murine anti-TNF-alpha monoclonal antibody was administered prophylactically. Together, these data suggest that SDZ MRL 953 enhances the resistance of mice against the toxicity of heat-k illed gram-negative bacteria and S. aureus, and attenuates host respon ses to living bacteria which may lead to irreversible shock and death. (C) 1994 Wiley-Liss, Inc.