Acute hypoxia decreases E. coli LPS-induced cytokine production and NF-kappaB activation in alveolar macrophages.
Reductions in alveolar oxygenation during lung hypoxia/reoxygenation (H/R) injury are common after gram-negative endotoxemia. However, the effects of H/R on endotoxin-stimulated cytokine production by alveolar macrophages are unclear and may depend upon thresholds for hypoxic oxyradical generation in situ. Here TNF-alpha and IL-1beta production were determined in rat alveolar macrophages stimulated with Escherichia coli lipopolysaccharide (LPS, serotype O55:B5) while exposed to either normoxia for up to 24h, to brief normocarbic hypoxia (1.5h at an atmospheric PO(2)=10+/-2mm Hg), or to combined H/R. LPS-induced TNF-alpha and IL-1beta were reduced at the peak of hypoxia and by reoxygenation in LPS+H/R cells (P<0.01) compared with normoxic controls despite no changes in reduced glutathione (GSH) or in PGE2 production. Both TNF-alpha mRNA and NF-kappaB activation were reduced by hypoxia that suppressed superoxide anion generation. Thus, dynamic reductions in the ambient PO(2) of alveolar macrophages that do not deplete GSH suppress LPS-induced TNF-alpha expression, IL-1beta production, and NF-kappaB activation even as oxyradical production is decreased.
Matuschak
George M
GM
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd., Saint Louis, MO 63104-1004, United States. matuscgm@slu.edu
Nayak
Ravi
R
Doyle
Timothy M
TM
Lechner
Andrew J
AJ
D000704:Analysis of Variance; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D013481:Superoxides; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D015232:Dinoprostone
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