diamide and Multiple-Organ-Failure

Endotoxin (lipopolysaccharide) stimulation of macrophages (M phi) induces the generation of toxic reactive oxygen intermediates (ROI); however, recent studies implicate intracellular redox changes in signal transduction pathways for cytokines. To test whether oxidant stress modulates M phi activation, rabbit alveolar M phi were exposed to the following: diamide (oxidizes intracellular glutathione); glucose oxidase (generates hydrogen peroxide); or xanthine oxidase (generates superoxide), before lipopolysaccharide. Supernatants were assayed for tumor necrosis factor (TNF) and cell lysates were assayed for procoagulant activity (PCA). TNF mRNA was analyzed by Northern blot. M phi exposure to diamide and glucose oxidase augmented TNF production, PCA expression, and TNF mRNA accumulation; however, xanthine oxidase exposure inhibited TNF production while augmenting PCA expression. M phi signal transduction can be enhanced by increasing cellular oxidant stress. The differential response of TNF versus PCA suggests the existence of distinct redox-sensitive signal transduction pathways. These data define a mechanism by which oxidants generated during inflammation may modulate M phi function.

Topics: Animals; Blood Coagulation Factors; Cells, Cultured; CHO Cells; Cricetinae; Dactinomycin; Diamide; Electrophoresis; Endotoxins; Glucose Oxidase; Glutathione; Humans; Infant, Newborn; Macrophages, Alveolar; Male; Multiple Organ Failure; NF-kappa B; Oxidants; Oxidation-Reduction; Oxidative Stress; Protein Synthesis Inhibitors; Rabbits; Reactive Oxygen Species; Respiratory Distress Syndrome, Newborn; RNA, Messenger; Superoxides; Tumor Necrosis Factor-alpha; Xanthine Oxidase