The failure to improve outcome of septic patients may reflect flawed hypotheses pertaining to the pathogenesis of sepsis. Alternatively, it may represent the use of clinically irrelevant experimental animal models. To address these issues, an alternative hypothesis is proposed. It is suggested that leukocyte activation in sepsis is initiated by a priming effect of minuscule doses of endotoxin on leukocytes for enhanced responsiveness to minute doses of inflammatory mediators (or vice versa) as opposed to activation by overwhelming doses of endotoxin per se. The experimental impetus of this hypothesis has been provided by a novel rat model of sepsis precipitated by the co-administration of PAF and LPS at doses 1/1000 lower than those previously used to elicit sepsis in the same species.
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