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 co ntribute to macrophage (MO) activation or dysregulation. In this study we compared the effects of transient anoxia and endotoxin pretreatmen t (LPS1) on MO mediator release with a second endotoxin stimulus (LPS2 ). Methods: In vitro cultures of murine peritoneal exudate MO were exp osed to 2 hours of hypoxic or normoxic conditions, then incubated 22 h ours under identical normoxic conditions +/-10 ng/mL of LPS1 pretreatm ent. During the final 24 hours all MOs were exposed to a range of LPS2 concentrations. The MO supernatants were assayed for tumor necrosis f actor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6), prostaglandin E2 (PGE2), nitric oxide (NO), and superoxide release. Results: LPS1 m arkedly inhibited MO TNF release by LPS2, but hypoxia had no effect on LPS2-triggered TNF release. Hypoxia increased MO IL-6 production in t he absence of LPS1, but inhibited the LPS1 augmentation seen under nor moxic conditions. Pretreatment with LPS1 increased NO production from LPS2 under normoxic conditions, but hypoxia inhibited this effect. Sup eroxide production increased by LPS1 under normoxic conditions, but hy poxia significantly inhibited superoxide release. Conclusions: The eff ects of transient anoxic exposure on LPS2-triggered MO function are ma rkedly different from the effects of pretreatment with septic stimuli (LPS1).