Sepsis followed by multiple organ failure is the leading cause of mortality and morbidity in the trauma/burn patient. This process is now recognized to be due to """"""""auto-destructive"""""""" inflammation, which may begin immediately after the trauma (burn). The initial generalized inflammatory response to local trauma, which appears to be oxidant induced, leads to a marked amplification of a subsequent septic insult. Our hypothesis is that multi- system organ failure (MSOF) is caused by activation of complement and/r by stimulation of proinflammatory cytokine and eicosanoid production which in turn results in oxidant induced tissue injury from tissue lipid perioxidation. Once inflammation is activated by complement/cytokines the process appears to progress. The mechanism of the interaction of complement, cytokines and oxidants remains undefined. We will use as our principal model the rat in which zymosan induced peritonitis leads to MSOF, not dependent on bacteria or endotoxin. The findings will be compared to the bacterial dependent rat cecal perforation model. we will test the hypothesis that zymosan peritonitis causes MSOF by activation of complement and.or by stimulation of proinflammatory cytokine an eicosanoid production with subsequent release of oxidants leading to tissue damage. Secondary hypotheses include; 1) In zymosan peritonitis, MSOF will occur only in association with increased levels of circulating proinflammatory cytokines and/or complement activation. 2) Complement activation stimulates proinflammatory cytokine production which leads to oxidant release. 3) Endotoxin levels which in turn might activate oxidant release in the portal or systemic blood will bear no relationship to cytokine levels, complement activation or MSOF. 4) Organ injury can be attenuated by blocking complement activation, modulating cytokine or eicosanoid production and by the use of antioxidants. Our long-term objective is to define prevention and treatment modalities as well as reliable markers of injury, which can be used to benefit injured man.
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