Oxidants augment endotoxin-induced activation of alveolar macrophages.
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.
Mendez
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Department of Surgery, University of Washington, Seattle 98104, USA.
Garcia
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I
Maier
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RV
D000818:Animals; D001779:Blood Coagulation Factors / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003609:Dactinomycin / Q000494:pharmacology; D003958:Diamide / Q000494:pharmacology; D004586:Electrophoresis / Q000379:methods; D004731:Endotoxins / Q000633:toxicity*; D005949:Glucose Oxidase / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009102:Multiple Organ Failure / Q000503:physiopathology; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D012127:Respiratory Distress Syndrome, Newborn / Q000503:physiopathology; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism / Q000494:pharmacology
D001779:Blood Coagulation Factors; D004731:Endotoxins; D016328:NF-kappa B; D016877:Oxidants; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003958:Diamide; D013481:Superoxides; D003609:Dactinomycin; D005949:Glucose Oxidase; D014969:Xanthine Oxidase; D005978:Glutathione