Mechanisms of the Lethal Action of Endotoxin and Endotoxin Hypersensitivity

Endotoxins (lipopolysaccharides, LPS) are endowed with a vast spectrum of biological activities that are both harmful and beneficiary for the host-organism. Many of these activities, e.g., mitogenic and polyclonal stimulation of antibody-producing cells, adjuvance activity or induction of prostaglandin and leucotriene synthesis in macrophages are not exclusively properties of endotoxin. They are also expressed by a number of other substances like zymosan (1, 22) or muramyl dipeptide (MDP) (9, 25, 26, 27) which are in some cases even more powerful inducers than endotoxin itself. Conversely, however, neither zymosan nor MDP elicit acute, hazardous effects that are in any way comparable to those seen in experimental endotoxin shock. Many activities of endotoxins are not necessarily side-effects of their toxic action as believed earlier but are induced independently by discrete structures in the lipid A. Evidence for this has been obtained in recent years by studying partial structures of natural and synthetic lipid A. We could thus show that a natural lipid A precursor structure containing 4 unsubstituted 3hydroxy-tetradecanoid acid residues (2 amide- and 2 ester linked) expresses significant lethal toxicity. This molecule was incapable of inducing the local Shwartzman reaction, the induction of which requires the additional substitution of at least one of the amide-linked 3-OH-tetradecanoic acids with hexadecanoic acid (12). Similarly a number of synthetic analogues and partial structures of lipid A, despite their low toxicity were potent in inducing proliferation and polyclonal antibody synthesis in mouse B-cells (16, 28, 29, 30). It thus becomes evident that many activities of endotoxin proceed independently and are based on self-contained mechanisms. For this reason, the elucidation of, for example, the mechanism of B-cell activation by endotoxin, although extremely important for the understanding of the effect of LPS on the immune system, and the mechanisms by which LPS interacts and triggers these cells, it will not necessarily disclose the mechanism of endotoxin induced lethality.