PREEXPOSURE TO HYPOXIA OR SEPTIC STIMULI DIFFERENTIALLY REGULATES ENDOTOXIN RELEASE OF TUMOR-NECROSIS-FACTOR, INTERLEUKIN-6, INTERLEUKIN-1, PROSTAGLANDIN-E2, NITRIC-OXIDE, AND SUPEROXIDE BY MACROPHAGES

Shock states with resulting inadequate cellular oxygen delivery may contribute to macrophage (MO) activation or dysregulation. In this study we compared the effects of transient anoxia and endotoxin pretreatment (LPS1) on MO mediator release with a second endotoxin stimulus (LPS2). Methods: In vitro cultures of murine peritoneal exudate MO were exposed to 2 hours of hypoxic or normoxic conditions, then incubated 22 hours under identical normoxic conditions +/-10 ng/mL of LPS1 pretreatment. During the final 24 hours all MOs were exposed to a range of LPS2 concentrations. The MO supernatants were assayed for tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6), prostaglandin E2 (PGE2), nitric oxide (NO), and superoxide release. Results: LPS1 markedly inhibited MO TNF release by LPS2, but hypoxia had no effect on LPS2-triggered TNF release. Hypoxia increased MO IL-6 production in the absence of LPS1, but inhibited the LPS1 augmentation seen under normoxic conditions. Pretreatment with LPS1 increased NO production from LPS2 under normoxic conditions, but hypoxia inhibited this effect. Superoxide production increased by LPS1 under normoxic conditions, but hypoxia significantly inhibited superoxide release. Conclusions: The effects of transient anoxic exposure on LPS2-triggered MO function are markedly different from the effects of pretreatment with septic stimuli (LPS1).