Protection from septic shock by neutralization of macrophage migration inhibitory factor
Protection from septic shock by neutralization of macrophage migration inhibitory factor
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DOI：
10.1038/72262
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发表时间：
2000-02-01
期刊：
影响因子：
82.9
通讯作者：
Glauser, MP
中科院分区：
文献类型：
--
作者：
Calandra, T;Echtenacher, B;Glauser, MP
由于包括抗肿瘤坏死因子（TNF）和抗白细胞介素（IL）-1制剂在内的所有研究性疗法都未能降低重症脓毒症患者的死亡率，因此确定脓毒性休克治疗的新靶点仍然至关重要。我们在此报告，巨噬细胞移动抑制因子（MIF）是脓毒性休克的关键介质。在细菌性腹膜炎小鼠的腹腔渗出液和体循环中检测到高浓度的MIF。在TNF-α基因敲除小鼠中进行的实验，可以在缺乏这种关键炎症细胞因子的情况下直接评估MIF在脓毒症中所起的作用。抗MIF抗体可保护TNF-α基因敲除小鼠免受盲肠结扎穿孔（CLP）诱导的致死性腹膜炎，这证明了MIF对脓毒症发病机制的内在作用。抗MIF抗体还可保护正常小鼠免受CLP和大肠杆菌诱导的致死性腹膜炎，即使在CLP后8小时才开始治疗也是如此。相反，重组MIF和大肠杆菌共同注射显著增加了腹膜炎的致死率。最后，在重症脓毒症或脓毒性休克患者的血浆中检测到高浓度的MIF。这些研究确定了MIF在脓毒性休克发病机制中的关键作用，并确定了一个新的治疗干预靶点。
Identification of new therapeutic targets for the management of septic shock remains imperative as all investigational therapies, including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly failed to lower the mortality of critically ill patients with severe sepsis. We report here that macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock. High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with bacterial peritonitis. Experiments performed in TNF alpha knockout mice allowed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation. Anti-MIF antibody protected TNF alpha knockout from lethal peritonitis induced by cecal ligation and puncture (CLP), providing evidence of an intrinsic contribution of MIF to the pathogenesis of sepsis. Anti-MIF antibody also protected normal mice from lethal peritonitis induced by both CLP and Escherichia coli, even when treatment was started up to 8 hours after CLP. Conversely co-injection of recombinant MIF and E. coli markedly increased the lethality of peritonitis. Finally, high concentrations of MIF were detected in the plasma of patients with severe sepsis or septic shock. These studies define a critical part for MIF in the pathogenesis of septic shock and identify a new target for therapeutic intervention.