Endotoxin is part of the outer membrane of the cell wall of gram-negative bacteria. It also is referred to as lipopolysaccharide (LPS), owing to its historical discovery. During the 1800s, it was understood that bacteria could secrete toxins into their environment, which were broadly known as “exotoxins.” The term endotoxin came about following the discovery that portions of the gram-negative bacteria itself can cause toxicity. Over the next 50 years, studies focused on endotoxin revealed that the actual molecule responsible for the effects of endotoxin was in fact LPS. Endotoxins largely are responsible for clinical manifestations of the infections induced by pathogenic gram-negative bacteria such as E. coli, Salmonella, Shigella, Pseudomonas, Neisseria, Haemophilus, and others. The goal of this chapter is to discuss the receptor, signaling pathway, and effect of LPS on endothelium.

LIPOPOLYSACCHARIDE STRUCTURE

LPS is comprised of a polysaccharide (“sugar”) chain and a lipid moiety, known as lipid A, the portion responsible for toxic effects (Figure 46.1). Lipid A is found in the exterior leaflet of the outer membrane. Lipid A is the most conserved portion of the molecule; however, it can vary according to the nature of fatty acid chains and its degree of phosphorylation. This portion is the biologically active component of LPS, because isolated lipid A or synthetic lipid A (free of contaminants) displays the same bioactivity as intact LPS in vitro and in vivo (1). Indeed, in bovine pulmonary artery endothelial cell (BPAEC) monolayers, lipid A has been shown to be the bioactive portion of LPS responsible for inducing changes in endothelial barrier function, with a dose-dependent increase in EC monolayer permeability comparable to that of native LPS (2).