MEDIATORS OF SEPTIC SHOCK - NEW APPROACHES FOR INTERRUPTING THE ENDOGENOUS INFLAMMATORY CASCADE

Objectives: To review the molecular pathogenesis of septic shock, with particular emphasis on the induction of cytokines by endotoxin. By un derstanding the mechanisms that result in the systemic inflammatory re sponse, novel clinical interventions may be more effectively studied. Data Sources. The English medical literature was reviewed, including h uman clinical trials, animal experiments, and in vitro studies elucida ting cellular and molecular interactions. Expert testimony from the Ro undtable Conference on Sepsis (Brussels, March 1992) was also used to synthesize emerging concepts and to ensure inclusion of ongoing invest igations. Study Selection: Emphasis on controlled experimental studies which elucidated the molecular and cellular interactions during sepsi s. Data Extraction: This study focused only on data that directly invo lved the induction and regulation of protein mediators of sepsis, espe cially tumor necrosis factor (TNF) and interleukin-1. Data concerning the role of TNF during health were extracted from the author's peer-re viewed data. Data Synthesis. Information concerning the many facets of the systemic inflammatory response was integrated into a chronologica l, clinically oriented model of cytokine induction during endotoxemia. Conclusions: The induction of inflammation during sepsis is a complex , but increasingly understood, biological cascade that is dependent on inter- and intracellular signaling. Novel biotherapies may improve pa tient outcome in sepsis by interrupting any or all points of signal tr ansduction.