In vivo and in vitro studies of bacterial endotoxin-membrane interactions and the effects of membrane-active agents.

Abstract

The characteristics of 51Cr-labelled E. coli endotoxin binding to human erythrocyte membranes in vitro have been investigated. A saturable component of binding was apparent at low endotoxin concentrations (less than 50 micrograms ml-1) relevant to its in vivo actions, while at higher concentrations binding was non-saturable and increased in linear fashion. Experiments examining the ability of unlabelled endotoxin to antagonize the binding of labelled toxin provided further evidence for these specific and non-specific modes of endotoxin-membrane interaction. Membrane-active agents previously shown to reduce endotoxin toxicity in vivo decreased endotoxin binding to erythrocyte membranes in vitro, with propranolol and pranolium being the most effective in this regard. Tissue distribution studies following administration of radiolabelled endotoxin to guinea-pigs showed a positive correlation between the accumulation of 51Cr-endotoxin in lung and elevations in plasma acid phosphatase activity, a measure of in vivo endotoxin toxicity. The in vivo accumulation of 51Cr-endotoxin in guinea-pig lung was reduced by prior treatment with (+)-propranolol or pranolium, paralleling the results of the in vitro binding studies. Our results suggest that membrane-active agents such as (+)-propranolol may be useful adjuncts to antimicrobial drugs in the therapy of gram-negative endotoxaemia.