THE ROLE OF HMGB-1 AS CYTOKINE IN INFECTION

用柑橘类黄酮橙皮苷（HES）预处理脂多糖（LPS）可抑制脂多糖（LPS）诱导的显色鲎反应。在LPS刺激前给药HES可显著降低肿瘤坏死因子(TNF)-α的产生，并呈剂量依赖性。腹腔感染108 CFU鼠伤寒沙门菌aroA前3小时治疗HES，可使小鼠从致死性休克中恢复，与lps无反应小鼠相似。经HES预处理后，肝脏和脾脏细菌数量及血浆LPS水平均显著降低。此外，HES显著抑制血浆TNF-a水平，减少肝脏凋亡细胞数量，使感染引起的凝血酶原时间、血小板数量等凝血因子的激活状态正常化。在沙门氏菌感染的内毒素休克模型中证实了柑橘黄酮柚皮苷的保护作用。腹腔（i.p.）感染10^8 CFU Salmo . More鼠伤寒杆菌aroA对脂多糖（LPS）有反应的小鼠造成致死性休克，而非无反应的小鼠。在感染前3小时给药1mg柚皮甙可防止致死性休克，与lps无反应小鼠相似。柚皮苷的保护作用具有时间和剂量依赖性。柚皮苷不仅使大鼠脾脏和肝脏细菌数量明显减少，而且血浆LPS水平也明显降低。柚皮苷显著抑制TNF-a，使感染引起的凝血因子如凝血酶原时间、纤维蛋白原浓度、血小板数量等活化状态正常化。有趣的是，柚皮苷抑制了感染引起的高水平可溶性CD14和高迁移率基团-1分子。研究了具有脂多糖（LPS）结合活性的抗生素多粘菌素B （PLB）对小鼠感染内毒素休克的保护作用。10^8个菌落形成单位的减毒鼠伤寒沙门菌aroA菌株感染小鼠可致死性内毒素休克。感染后1小时（p.i.）用PLB治疗可显著降低死亡率和肝脏细菌数量。此外，用plb1h p.i.治疗可导致血浆LPS水平在早期短暂升高和逐渐下降。尽管血浆中sCD14和高迁移率组盒染色体蛋白-1 （HMGB-1）的水平随着感染的进展而升高，但PLB治疗1小时后，血浆中sCD14和HMGB-1水平的升高被下调。然而，抗cd14单克隆抗体治疗在3小时和6小时后并没有阻断致死性休克。有趣的是，PLB治疗6小时后没有显示出任何保护作用。表明存在有效PLB行动的时间窗口。少

Lipopolysaccharide (LPS)-elicited chromogenic Limulus reaction was suppressed by pretreating LPS with a citrus flavonoid hesperidin (HES). Administration of HES to mice before LPS challenge significantly reduced tumor necrosis factor (TNF)-α production in a dose-dependent manner. Treatment of HES 3 h before intraperitoneal (i.p.) infection with 108 CFU Salmonella typhimurium aroA resulted in rescue from lethal shock as similar to LPS-nonresponder mice. Not only bacterial numbers in livers and spleens but also plasma LPS levels significantly decreased by pretreating with HES. In addition, HES markedly suppressed plasma TNF-a levels, decreased the number of apoptotic cells in livers and normalized the activated states of blood coagulation factors such as prothrombin time and platelet numbers caused by infection.The protective effect of Citrus flavanone naringin was demonstrated in an endotoxin shock model based on Salmonella infection. Intraperitoneal (i.p.) infection with 10^8 CFU Salmo … More nella typhimurium aroA caused lethal shock in lipopolysaccharide (LPS)-responder but not -nonresponder mice. Administration of 1 mg naringin 3 h before infection resulted in protection from lethal shock, similar to LPS-nonresponder mice. The protective effect of naringin was time- and dose-dependent. Treatment with naringin resulted not only in a significant decrease in bacterial numbers in spleens and livers, but also a decrease in plasma LPS levels. In addition, naringin markedly suppressed TNF-a and normalized the activated states of blood coagulation factors such as prothrombin time, fibrinogen concentration and platelet numbers caused by infection. Interestingly, treatment with naringin suppressed high levels of soluble CD14 and high mobility group-1 molecule caused by infection.The protective effects of an antibiotic polymyxin B (PLB), having lipopolysaccharide (LPS)-binding activity, on infection-induced endotoxin shock in mice were investigated. Infection with 10^8 colony forming units of an attenuated Salmonella typhimurium aroA strain caused lethal endotoxin shock to ddY mice. Treatment with PLB 1 h post infection (p.i.) resulted in significant reduction of mortality and bacterial numbers in livers. In addition, treatment with PLB 1 h p.i. resulted in a transient increase at the early stage and gradual decline in plasma LPS levels. Although plasma levels of sCD14 and high mobility group box chromosomal protein-1 (HMGB-1) increased according with progression of infection, increases in plasma levels of sCD14 and HMGB-1 were downregulated by treatment with PLB 1 h p.i. However, the lethal shock was not blocked by treatment with anti-CD14 monoclonal antibody at 3 h and 6 h p.i. Interestingly, administration of PLB 6 h p.i. did not show any protective activities, indicating that a time window for effective PLB action is present. Less