Most therapies for gram-negative sepsis have their foundation in two generally believed assumptions: (1) that lipopolysaccharide (LPS) is important in the pathogenesis of gram-negative sepsis in humans, and (2) that part or all of this pathophysiology is mediated by a complex secondary inflammatory response. These assumptions are based on the findings that much of the pathophysiology of gram-negative sepsis can be reproduced by administration of purified LPS or a variety of LPS-free recombinant mediators and that many of these changes can be blocked in vitro and in vivo using drugs that block LPS or the activity of the mediators. Strictly speaking, to prove these assumptions, it will be necessary to demonstrate decreased morbidity or mortality in humans with specific agents that block LPS or components of the inflammatory cascade. So far, this has not been accomplished. There are, however, a number of agents under development that may soon allow these two assumptions to be tested. This article focuses on therapeutic approaches to blocking LPS.

LPS, phospholipids, and outer membrane proteins are dominant components of the gram-negative bacterial outer membrane. LPS is a structurally complex molecule that consists of a highly variable polysaccharide chain (the O-antigen) covalently attached to lipid A by a linking oligosaccharide. The linking oligosaccharide is moderately conserved, and lipid A is highly conserved. Because of their conserved structure, the oligosaccharide and lipid A are sometimes considered together and called the core glycolipid. Lipid A is the toxic moiety of LPS.

There has been an explosion of new information over the last several years regarding the interactions of LPS with proteins and cells. Blocking sepsis at the bacterial toxin level is appealing because it is upstream, so that the secondary pathologic inflammatory cascade may be limited or prevented. A variety of antiendotoxin strategies have been proposed. Therapies under investigation include agents that bind and neutralize LPS, agents or systems that enhance LPS clearance, and agents that inhibit LPS interaction with serum elements or cellular receptors.