Hypersensitivity to endotoxin and mechanisms of host-response.

It was shown here that the lethal activity of endotoxin may be considerably enhanced in experimental animals treated with different agents. Some of these agents represent killed bacteria, bacterial products or hepatotoxic agents and their sensitizing effects may be relevant to the sensitization seen during gram-negative infections. This study provided direct evidence that macrophages are cells mediating the lethal activity of endotoxin and that the direct interaction of LPS with macrophages is the first step in its initiation. Further, TNF is a macrophage mediator responsible for the induction of lethality. In normal animals as well as in the various sensitization models investigated, TNF alone was sufficient to induce lethality. Therefore, the stimulation of macrophages by LPS to produce TNF is a mechanism common to diverse lethality models. It would seem therefore that the complexity of endotoxicity in gram-negative infections is related primarily to the complexicity of the factors altering the susceptibility of the host rather than to be actual mechanisms of the lethal action of endotoxin. The identification of the factors leading to sensitization and their underlying mechanisms would contribute to a better understanding of the complex phenomenon endotoxicity.