Hypoxia/reoxygenation affects endotoxin tolerance

Pretreatment of animals with sublethal doses of endotoxin renders them tolerant to subsequent endotoxin challenge. Tissue hypoxia following infection may potentiate the immune response to injury. To evaluate the effect of hypoxia/reoxygenation (H/R) on endotoxin tolerance by macrophages, adult CBA mice were pretreated with 10 micrograms/animal of LPS injected intraperitonealy. Five days later, animals were subjected to 16 hr of hypoxia followed by 2 hr of reoxygenation. Harvested peritoneal macrophages were cultured and either stimulated in vitro with LPS or left unstimulated. Culture supernatants collected at 2, 4, and 6 hr were assayed for tumor necrosis factor (TNF), prostaglandin E2 (PGE2), and nitric oxide (NO). Control animals underwent the same procedures, but were maintained in normoxia. H/R resulted in significantly greater TNF production but significantly lower PGE2 and NO production, P < 0.05 by ANOVA. These data suggest that LPS-induced tolerance of macrophages to the same stimulus is abated by H/R.