ACTION MECHANISMS OF HMG-1 ON ENDOTOXIN SHOCK

(1)研究革兰氏阴性菌感染过程中释放的不同类型脂多糖的清除量和活性。给小鼠静脉注射高纯度制剂时，粗制剂的清除速度比光滑形式的快得多。小鼠腹腔感染108CFU E.coliO111：B4后，血浆中可检测到较高水平的内毒素，且持续时间较长。这些结果表明，在感染过程中，血浆内毒素水平持续升高，继而出现更强的宿主反应，提示在分析脂多糖诱导的宿主反应时，应考虑内毒素感染小鼠与感染小鼠之间的差异。(2)在一种新的内毒素休克模型上，观察了磷霉素(FOF)和亚胺培南(IPM)对内毒素休克的治疗作用。使用…进行治疗感染后1h再给药1h，小鼠脾、肝细菌数量明显减少，提示其抗菌活性可能与抑制感染性致死性休克密切相关。(3)研究hMG-1在脂多糖和肿瘤坏死因子-α致敏小鼠致死性休克中的作用。致敏小鼠注射肿瘤坏死因子-α后5.5h血浆中即可检测到hMG-1，而BALB/Lps^d小鼠则在6h内检测到hMG-1，但6h后几乎全部死亡。这种时间依赖性现象与血清天冬氨酸氨基转移酶水平升高和肝脏中出现凋亡细胞有关。从濒临死亡的小鼠身上提取的混合血浆，相当于大约200μg重组小鼠hMG-1，没有导致GalN致敏小鼠发生致死性休克。这些数据表明，在GalN致敏模型中，HMG-1并不是致死性的决定性因素。较少

(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