Oxygen radicals—An important mediator of sepsis and septic shock

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Abstract
Summary There is considerable evidence to implicate aggressive species of oxygen in the pathogenesis of organ dysfunction consequent to sepsis and septic shock. The inflammatory process appears to participate ubiquitously in this setting. A characteristic of inflammation is the involvement of activated neutrophils and their generation of aggressive oxygen species. Such species may both directly injure cells proximal to the oxidant generating cells, and may inactivate any proteolytic mechanisms normally protective against proteolytic injury caused by neutrophil elastase and other proteolytic enzymes released during inflammation. The offending agent in sepsis is most commonly envisioned as bacterial lipopolysaccharide, or endotoxin. Infusion of endotoxin into animals can reproduce much of the pathophysiology of sepsis and septic shock. In addition, administration of endotoxin to cultured cells, particularly endothelial cells, can cause responses consistent with a sequence of events that occurs in intact animals and humans. In both experimental models, it appears that aggressive oxygen species are important actors in the scenario eventuating in cell or organ injury. Of importance, the toxic consequences of these free radicals probably occurs in relatively protected spaces, including microenvironments created by close adherence between inflammatory cells and endothelial cells and the cell interior. For those reasons, the potential for antioxidants as therapy should include consideration of the volume of distribution of such substances. It is probably important that antioxidants access excluded spaces including cell interiors in order to have their maximum effect in this setting. We have studied in a preliminary way the effects of n-acetyl-cysteine, a highly permeable free radical scavenger and antioxidant, in patients with established ARDS. The preliminary data suggest that this antioxidant may indeed be beneficial and a larger prospective study is underway. Novel, new therapies are on the horizon. The explosion of knowledge concerning the manipulation of DNA and the technologies for delivering functioning foreign genes to intact organisms promise completely new categories of therapies which may be applicable in sepsis and septic shock as well as the acute and subacute clinical situations. Eventual realization of the potential of such therapy must await additional basic and clinical investigation.

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