Bacterial endotoxin and current concepts in the diagnosis and treatment of endotoxaemia

Abstract

Background The study of endotoxin began at the end of the 19th century when Richard Pfeiffer, a pupil of Robert Koch, found that lysates of heat-inactivated Vibrio cholerae contained a toxic principle which was capable of inducing shock and death in experimental animals. He termed this heat-stable toxin “endotoxin” to distinguish it from the heatlabile exotoxins which were actively secreted by live V. cholerae. Around the same time two other scientists, Eugenio Centanni and Hans Buchner, independently isolated the same toxin. Centanni made two important contributions. First, he observed that this toxin could be isolated from lysates of many different gram-negative bacteria, but never from similar preparations of gram-positive bacteria. Second, he drew attention to the remarkable pyrogenic properties of endotoxin. Buchner was the first to demonstrate the association of endotoxin with leucocytosis and altered host immunity. It was not until 1935 that Boivin and Messrobeanu, using a method of trichloracetic extraction, determined that the endotoxic activity of gramnegative bacterial lysates resided in an outermembrane macromolecular complex of protein, lipid and polysaccharide. Two decades later Westphal and Luderitz commenced their classic studies on the biochemistry of endotoxin. Protein-free lipopolysaccharide (LPS), prepared by phenolwater extraction and purified, possessed all the properties of crude endotoxin. Further separation of LPS into a water-soluble polysaccharide fraction and a chloroform-soluble lipid fraction led to the finding that the biological activity of endotoxin resided in the lipid moiety, now termed Lipid A. More recently Lipid A has been chemically synthesised and both natural and synthetic molecules display identical activities.