Endotoxin as a drug target

Objective. To review the preclinical and clinical evidence that antiendotoxin therapeutic strategies are potentially useful in the prevention and treatment of septic shock. Study design. A critical review of the literature over the past 30 yrs relating basic and clinical research on the therapeutic value of endotoxin as a target for the prevention and treatment of severe sepsis and septic shock. Main Results: Bacterial endotoxin is a potent and predominant microbial mediator that induces an intense inflammatory and procoagulant response by elements of the innate immune response. This macromolecule is. capable of inducing lethal septic shock in experimental animals, and a large number of preclinical studies consistently demonstrate the survival advantage of endotoxin inhibition in experimental models of sepsis. Clinical studies indicate that endotoxin may be found in the systemic circulation in the majority of humans with septic shock. Endotoxemia is largely independent of the nature of the infecting microorganism despite the fact that this molecule is specifically found in the outer membrane of Gram-negative bacteria only. Antiendotoxin strategies studied thus far have not provided reproducible survival benefits in clinical trials in septic patients. Conclusions. Despite compelling evidence of the critical importance of endotoxin in the pathogenesis of Gram-negative bacterial sepsis in preclinical investigations and numerous clinical interventional trials, the utility of antiendotoxin approaches to significantly reduce the mortality rate in human septic shock remains unproven. Ongoing clinical trials with specific endotoxin inhibitors should determine the potential value of this therapeutic approach to the management of septic shock.