Antioxidants attenuate endotoxin-induced activation of alveolar macrophages.
BACKGROUND
Endotoxin (lipopolysaccharide [LPS]) stimulation of tissue-fixed macrophages induces the generation of toxic oxidants. However, recent studies also implicate redox changes in both the signal transduction pathways for cytokine genes and the generation of physiologically active arachidonic acid metabolites. Because cytokines and arachidonic acid metabolites initiate and perpetuate deleterious systemic inflammatory responses, we tested whether macrophage activation could be modulated by antioxidants.


METHODS
Rabbit alveolar macrophages were obtained by bronchoalveolar lavage, isolated, treated with the antioxidants vitamin E or N-acetylcysteine (NAC), and stimulated with an optimal dose of LPS (10 ng/ml). Assays were performed for tumor necrosis factor (TNF), procoagulant activity, and prostaglandin E2. Total cellular RNA was extracted for Northern blot analysis of TNF messenger RNA.


RESULTS
Exposure of the macrophage to the antioxidants vitamin E and NAC inhibited TNF production, accumulation of TNF messenger RNA, procoagulant activity expression, and prostaglandin E2 production.


CONCLUSIONS
Macrophage signal transduction of LPS is dependent on the generation of reactive oxygen intermediates that can be blocked both at the level of the lipid membrane (vitamin E) and at the intracellular level (NAC). This suggests a potential therapeutic role for antioxidants is disease states such as adult respiratory distress syndrome and multiple organ failure syndrome, which are characterized by excessive macrophage activation.
Mendez
C
C
Department of Surgery, University of Washington, Seattle 98195, USA.
Garcia
I
I
Maier
R V
RV
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D004731:Endotoxins / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014810:Vitamin E / Q000494:pharmacology*
D000975:Antioxidants; D001779:Blood Coagulation Factors; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; C045072:macrophage procoagulant activity; D014810:Vitamin E; D015232:Dinoprostone; D000111:Acetylcysteine