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 sepsis 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 cytokine secretion induced by lipopolysaccharide (LPS) administration in rats. Treatment with MDL 101,002(10-60 ng/kg, i.p.) 30 min prior to an LPS challenge resulted in a dose-dependent reduction in several markers indicative of organ dysfunction and mortality. MDL 101,002 markedly decreased LPS-induced liver and kidney damage as indicated by serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or urea and creatinine, respectively. MDL 101,002 also prevented LPS-induced pulmonary edema, but did not prevent leukopenia and only partially reduced thrombocytopenia. Associated with these improvements in organ dysfunction and survival was a modest decrease in LPS-stimulated interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) 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 and suggest that free radical scavengers could reduce the mortality consequent to sepsis by decreasing organ dysfunction, at least in part, through a reduction in free radical stimulated cytokine secretion.
Downs
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TR
Marion Merrell Dow Research Institute, Cincinnati, OH 45215, USA.
Dage
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French
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JF
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D004926:Escherichia coli / Q000378:metabolism*; D007375:Interleukin-1 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D009589:Nitrogen Oxides / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C091566:3,4-dihydro-3,3-dimethylisoquinoline-N-oxide; D000975:Antioxidants; D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D007546:Isoquinolines; D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D014409:Tumor Necrosis Factor-alpha; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase