REDUCTION IN ENDOTOXIN-INDUCED ORGAN DYSFUNCTION AND CYTOKINE SECRETION BY A CYCLIC NITRONE ANTIOXIDANT

Multiple organ dysfunction (MOD) is the leading cause of mortality in septic patients with circulatory shock. Recent evidence suggests that the overproduction of the cytokine, tumor necrosis factor-alpha(TNF), and oxygen free radical molecules may mediate the progression of sepsi s to MOD and death. In this study, we have examined the ability of MDL 101,002, a free radical scavenger, to reduce organ dysfunction and cy tokine secretion induced by lipopolysaccharide (LPS) administration in rats. Treatment with MDL 101,002(10-60 mg/kg, i.p.) 30 min prior to a n LPS challenge resulted in a dose-dependent reduction in several mark ers indicative of organ dysfunction and mortality. MDL 101,002 markedl y decreased LPS-induced liver and kidney damage as indicated by serum levels of aspartate aminotransferase (AST) and alanine aminotransferas e (ALT) or urea and creatinine, respectively. MDL 101,002 also prevent ed LPS-induced pulmonary edema, but did not prevent leukopenia and onl y partially reduced thrombocytopenia. Associated with these improvemen ts in organ dysfunction and survival was a modest decrease in LPS-stim ulated interIeukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 b eta) secretion and a marked (> 90%) inhibition of TNF secretion by MDL 101,002. The data are consistent with a role for oxygen free radicals in the development of endotoxin-induced organ dysfunction and shock a nd suggest that free radical scavengers could reduce the mortality con sequent to sepsis by decreasing organ dysfunction, at least in part, t hrough a reduction in free radical stimulated cytokine secretion.