Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blood Coagulation Factors / drug effects
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Blood Coagulation Factors / metabolism
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CHO Cells
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Cells, Cultured
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Cricetinae
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Dactinomycin / pharmacology
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Diamide / pharmacology
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Electrophoresis / methods
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Endotoxins / toxicity*
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Glucose Oxidase / metabolism
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Glucose Oxidase / pharmacology
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Glutathione / metabolism
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Humans
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Infant, Newborn
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Macrophages, Alveolar / drug effects
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Macrophages, Alveolar / metabolism*
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Male
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Multiple Organ Failure / physiopathology
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NF-kappa B / drug effects
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NF-kappa B / metabolism
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Oxidants / pharmacology*
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Oxidation-Reduction
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Oxidative Stress / drug effects
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Oxidative Stress / physiology*
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Protein Synthesis Inhibitors / pharmacology
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RNA, Messenger / metabolism
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Rabbits
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Reactive Oxygen Species / metabolism
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Respiratory Distress Syndrome, Newborn / physiopathology
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Superoxides / metabolism
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Tumor Necrosis Factor-alpha / drug effects
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Xanthine Oxidase / metabolism
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Xanthine Oxidase / pharmacology
Substances
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Blood Coagulation Factors
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Endotoxins
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NF-kappa B
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Oxidants
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Protein Synthesis Inhibitors
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RNA, Messenger
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Reactive Oxygen Species
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Tumor Necrosis Factor-alpha
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Diamide
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Superoxides
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Dactinomycin
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Glucose Oxidase
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Xanthine Oxidase
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Glutathione