Endotoxin in the pathogenesis of sepsis

Abstract

The word 'sepsis' is a descriptive term that denotes the clinical syndrome resulting from the activation of an innate host response to infection. Sepsis is a useful concept that underlines the fact that the morbidity of serious infection arises through the response of the host, rather than through intrinsic cytopathic effects of the microorganism. However, it has proven inadequate as a means to delineate a population of patients who might benefit from therapies that modulate this response. The syndrome is variable in its clinical expression, and not specific for infection as a cause. Emerging insights into the biology of the innate host immune response reveal that the cellular response can be evoked by a variety of stimuli - including both microbial products and host-derived molecules that are normally intracellular - that signal danger to the host. The disconnect between concept and disease that has hampered the conduct of clinical trials is nicely exemplified in the host response to endotoxin. Endotoxemia occurs in many patients with sepsis, but also in many clinical settings that are noninfectious in nature. Moreover, the biologic behavior of endotoxin resembles that of a hormone more than that of a toxin, suggesting that low level endotoxemia may, under some circumstances, be beneficial. Future studies of antiendotoxin strategies in acute illness are more likely to succeed if they recruit patients with endotoxemia, and titrate therapy to an optimal level.