Waring P M, Waring L J, Billington T, Metcalf D
Cancer Research Unit, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia.
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1337-41. doi: 10.1073/pnas.92.5.1337.
Leukemia inhibitory factor (LIF) has recently been associated with septic shock in humans. In this study we sought to determine, in mice, the role of LIF in septic shock. During sublethal endotoxemia, serum LIF levels, as determined by radio-receptor competition assay, peaked at 2 h and were low (3 ng/ml), whereas in lethal Escherichia coli septic shock serum LIF levels rose progressively (> 30 ng/ml) in the premorbid phase coincident with the development of tissue injury. Single i.v. injections of high doses (up to 50 micrograms per mouse) of recombinant murine LIF had no obvious acute detrimental effects, whereas continued i.p. administration (30 micrograms per mouse per day) for 3-4 days induced a fatal catabolic state without evidence of preceding hemodynamic collapse or shock. Simultaneous or subsequent administration of high doses of LIF had no effect on mortality from sublethal and lethal E. coli septic shock, whereas prior administration conferred significant protection against lethality (P << 0.001 by log-rank test), an effect that was dose and interval dependent. This protective effect resembled endotoxin tolerance and was characterized by suppression of E. coli-induced serum tumor necrosis factor concentration (P < 0.05), reduction in the number of viable bacteria (P < 0.05), and prevention of sepsis-induced tissue injury. These observations suggest that systemic LIF production is part of the host response to both endotoxin and sepsis-induced tissue injury.
白血病抑制因子（LIF）最近被认为与人类脓毒性休克有关。在本研究中，我们试图确定LIF在小鼠脓毒性休克中的作用。在亚致死性内毒素血症期间，通过放射受体竞争测定法测定的血清LIF水平在2小时达到峰值且较低（3 ng/ml），而在致死性大肠杆菌脓毒性休克中，血清LIF水平在发病前期随着组织损伤的发展而逐渐升高（> 30 ng/ml）。单次静脉注射高剂量（每只小鼠高达50微克）的重组鼠LIF没有明显的急性有害作用，而持续腹腔注射（每只小鼠每天30微克）3 - 4天会诱导一种致命的分解代谢状态，且无先前血流动力学崩溃或休克的迹象。同时或随后给予高剂量的LIF对亚致死性和致死性大肠杆菌脓毒性休克的死亡率没有影响，而预先给予则能显著保护小鼠免于死亡（对数秩检验P << 0.001），这种作用具有剂量和间隔依赖性。这种保护作用类似于内毒素耐受，其特征为抑制大肠杆菌诱导的血清肿瘤坏死因子浓度（P < 0.05）、减少活菌数量（P < 0.05）以及预防脓毒症诱导的组织损伤。这些观察结果表明，全身LIF的产生是宿主对内毒素和脓毒症诱导的组织损伤反应的一部分。
