ACTION MECHANISMS OF HMG-1 ON ENDOTOXIN SHOCK

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(1) The clearance and activity of different types of lipopolysaccharide (LPS) released during infection with gram-negative bacteria were investigated. When highly purified preparations were administered intravenously to mice, the clearance of rough-form LPS preparations much faster than that of a smooth-form LPS. After intraperitoneal infection with 10^8 CFU E.coli O111 : B4, relatively high levels of LPS were detected in the plasma of infected mice and persisted for a long time. These results indicate that continuously higher levels of plasma LPS followed by stronger host responses occur during infection and suggest that these differences between LPS-administered and infected mice should be taken into consideration when analyzing host responses induced by LPS.(2) In a novel model for endotoxin shock that was caused by intraperitoneal infection with 10^8 CFU of attenuated Salmonella typhimurium, therapeutic effects of fosfomycin (FOF) and imipenem (IPM) were investigated. Treatment wit … More h FOF 1 h postinfection resulted in significant decreases in bacterial numbers in spleen and liver, suggesting that the antimicrobial activity of FOF seems to closely correlate to suppression of infection-induced lethal shock.(3) The role of HMG-1 in LPS- and TNF-α-induced lethal shock in galactosamine (GalN)-sensitized mice was investigated. When GalN-sensitized mice were injected with TNF-α, HMG-1 was seen at 5.5 h in plasma of BALB/c mice and at 6 h in BALB/lps^d mice, although almost GalN-sensitized BALB/c mice died by 6 h after challenge. The time-dependent phenomenon correlated with elevated serum aspartate aminotransferase levels and the appearance of apoptotic cells in livers. Administration of pooled plasma, equivalent to approximately 200 μg recombinant murine HMG-1, taken from mice on the verge of near death, did not result in induction of lethal shock in GalN-sensitized mice. Taken together with the late appearance of HMG-1 in moribund mice, these data suggest that HMG-1 does not decisively contribute to lethality in the GalN sensitization model. Less