Alterations in alveolar macrophage (AM) function during sepsis-induced hypoxia may influence tumor necrosis factor (TNF) secretion and the progression of acute lung injury. Nuclear factor (NF)-B is thought to regulate the expression of endotoxin [lipopolysaccharide (LPS)]-induced inflammatory cytokines such as TNF, and NF-B may also be influenced by changes in O₂ tension. It is thus proposed that acute changes in O₂ tension surrounding AMs alter NF-B activation and TNF secretion in these lung cells. AM-derived TNF secretion and NF-B expression were determined after acute hypoxic exposure of isolated Sprague-Dawley rat AMs. Adhered AMs (10⁶/ml) were incubated (37°C at 5% CO₂) for 2 h with LPS (Pseudomonas aeruginosa, 1 µg/ml) in normoxia (21% O₂-5% CO₂) or hypoxia (1.8% O₂-5% CO₂). AM-derived TNF activity was measured with a TNF-specific cytotoxicity assay. Electrophoretic mobility shift and supershift assays were used to determine NF-B activation and to identify NF-B isoforms in AM extracts. In addition, mRNAs for selected AM proteins were determined with RNase protection assays. LPS-exposed AMs in hypoxia had higher levels of TNF (P < 0.05) and enhanced expression of NF-B (P < 0.05); the predominant isoforms were p65 and c-Rel. Increased mRNA bands for TNF-, interleukin-1, and interleukin-1 were also observed in the hypoxic AMs. These results suggest that acute hypoxia in the lung may induce enhanced NF-B activation in AMs, which may result in increased production and release of inflammatory cytokines such as TNF.

transcription factor; nuclear factor-B; oxygen; acute lung injury; cytokines

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