Reversing established sepsis with antagonists of endogenous high-mobility group box 1
Reversing established sepsis with antagonists of endogenous high-mobility group box 1
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DOI：
10.1073/pnas.2434651100
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发表时间：
2004-01-06
影响因子：
11.1
通讯作者：
Tracey, KJ
中科院分区：
文献类型：
--
作者：
Yang, H;Ochani, M;Tracey, KJ
尽管重症监护治疗和抗生素取得了重大进展，但严重脓毒症仍占美国每年所有死亡人数的9%。脓毒症的病理学后遗症的特征在于全身炎症反应，但靶向特定早期炎症介质[肿瘤坏死因子（TNF）和IL-1 β]的实验性治疗在临床上尚未证明有效。我们最近发现高迁移率族蛋白1（HMGB 1）是内毒素诱导的致死性的晚期介质，相对于TNF和IL-1 β，它表现出明显延迟的动力学。在这里，我们报告说，血清HMGB 1水平显着增加，在一个标准化的小鼠脓毒症模型，手术诱导腹膜炎后18小时开始。HMGB 1活性的特异性抑制[使用任一抗HMGB 1抗体（每只小鼠600 μ g）或DNA结合A盒（每只小鼠600 μ g）]在手术诱导腹膜炎后24小时开始显著增加存活率（非免疫IgG处理的对照= 28%对比抗HMGB 1抗体组= 72%，P < 0.03; GST对照蛋白= 28%对比A box = 68%，P < 0.03）。用任一HMGB 1拮抗剂处理的动物被保护免于器官损伤的发展，如通过血清肌酐和血尿素氮水平的改善所证明的。这些观察结果表明，内源性HMGB 1的特异性抑制在治疗上逆转了已建立的脓毒症的致死性，表明HMGB 1抑制剂可以在临床相关的时间范围内施用。
Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1beta] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1beta. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 mug per mouse) or the DNA-binding A box (600 mug per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.