Acute hypoxia increases alveolar macrophage tumor necrosis factor activity and alters NF-κB expression

SK Leeper-Woodford, K Detmer - American Journal of …, 1999 - journals.physiology.org
SK Leeper-Woodford, K Detmer
American Journal of Physiology-Lung Cellular and Molecular …, 1999journals.physiology.org
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)-κB is thought to regulate the expression of endotoxin [lipopolysaccharide
(LPS)]-induced inflammatory cytokines such as TNF, and NF-κB may also be influenced by
changes in O2tension. It is thus proposed that acute changes in O2 tension surrounding
AMs alter NF-κB activation and TNF secretion in these lung cells. AM-derived TNF secretion …
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)-κB is thought to regulate the expression of endotoxin [lipopolysaccharide (LPS)]-induced inflammatory cytokines such as TNF, and NF-κB may also be influenced by changes in O2tension. It is thus proposed that acute changes in O2 tension surrounding AMs alter NF-κB activation and TNF secretion in these lung cells. AM-derived TNF secretion and NF-κB 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-κB activation and to identify NF-κB 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-κB (P < 0.05); the predominant isoforms were p65 and c-Rel. Increased mRNA bands for TNF-α, interleukin-1α, and interleukin-1β were also observed in the hypoxic AMs. These results suggest that acute hypoxia in the lung may induce enhanced NF-κB activation in AMs, which may result in increased production and release of inflammatory cytokines such as TNF.
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