LEUKEMIA INHIBITORY FACTOR PROTECTS AGAINST EXPERIMENTAL LETHAL ESCHERICHIA-COLI SEPTIC SHOCK IN MICE

Leukemia inhibitory factor (LIF) has recently been associated with sep tic shock in humans. In this study we sought to determine, in mice, th e role of LIP 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. i njections of high doses (up to 50 mu g per mouse) of recombinant murin e LIF had no obvious acute detrimental effects, whereas continued i.p. administration (30 mu g per mouse per day) for 3-4 days induced a fat al catabolic state without evidence of preceding hemodynamic collapse or shock, Simultaneous or subsequent administration of high doses of L IF 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 d ose and interval dependent. This protective effect resembled endotoxin tolerance and was characterized by suppression of E. coli-induced ser um tumor necrosis factor concentrations (P < 0.05), reduction in the n umber 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 tis sue injury.