Disparities in efficacies of anti-LPS agents in burned mouse models of LPS intoxication versus Gram-negative sepsis

Abstract

Results of anti-LPS treatments in LPS-intoxicated animals have been promising, but use of anti-LPS agents in clinical trials of sepsis have been disappointing. The purpose of this study was to determine if treatment results in intoxicated animals would hold in animal models of sepsis. Burned (15% body surface) mice were injected immediately postburn with either LPS (= intoxication) or with bacteria, which lead to sepsis. When possible, bacteria used were of the same genus and species as bacteria from which LPS was extracted for intoxication studies. Polymyxin, monophosphoryl lipid A or monoclonal antibody E5 given 1 h postburn, each protected long term against death from endotoxin intoxication. However, in septic mice, monophosphoryl lipid A and monoclonal antibody E5 did not improve survival, and polymyxin showed only transient improvement. Hence, animal models of LPS intoxication may not be optimal for testing anti-sepsis agents; use of such models, rather than of models of sepsis, may account partly for the overly optimistic expectations for anti-sepsis agents which have recently been shown to be rather ineffective in clinical trials.