Acute hypoxia decreases E. coli LPS-induced cytokine production and NF-κB activation in alveolar macrophages

Abstract

Reductions in alveolar oxygenation during lung hypoxia/reoxygenation (H/R) injury are common after gram-negative endotoxemia. However, the effects of H/R on endotoxin-stimulated cytokine production by alveolar macrophages are unclear and may depend upon thresholds for hypoxic oxyradical generation in situ. Here TNF-α and IL-β production were determined in rat alveolar macrophages stimulated with E. coli lipopolysaccharide (LPS, serotype O55:B5) while exposed to either normoxia for up to 24 h, to brief normocarbic hypoxia (1.5 h at an atmospheric PO 2 = 10 ± 2 mm Hg), or to combined H/R. LPS-induced TNF-α and IL-β were reduced at the peak of hypoxia and by reoxygenation in LPS + H/R cells (P < 0.01) compared with normoxic controls despite no changes in reduced glutathione (GSH) or in PGE2 production. Both TNF-α mRNA and NF-κB activation were reduced by hypoxia that suppressed superoxide anion generation. Thus, dynamic reductions in the ambient PO2 of alveolar macrophages that do not deplete GSH suppress LPSinduced TNF-α expression, IL-β production, and NF-κB activation even as oxyradical production is decreased.

Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis

“…Similar results were also seen for the TLR9 agonist CpG (figure 4B). In contrast, hypoxia compromised TLR4 agonist LPS-induced inflammatory cytokine production (figure 4C), which was consistent with previously reported results in macrophages 17. One potential mechanism is that hypoxia might diminish TLR4 expression in RASF, as reported by Ishida et al 18…”

Myeloid differentiation protein 2 silencing decreases LPS-induced cytokine production and TLR4/MyD88 pathway activity in alveolar macrophages

“…Cell sensitivity to LPS is likely to be controlled by the modulation of TLR4 biosynthesis or activity through changes in sensitivities to the signals initiated or received by TLR4. It is well confirmed that blocking MD-2 or TLR4/MD-2 by antagonists may help to attenuate the severity of inflammation induced by LPS-activated AMs [10][11][12][13]. Taken together, MD-2 is an interesting and logical target for pharmacological intervention to prevent or attenuate excessive lung inflammation.…”

Immunologic Consequences of Hypoxia during Critical Illness

“…In addition, hypoxia increases the production of pro-inflammatory cytokines upon stimulation with the toxins lipopolysaccharide (LPS)- or Phytohaemagglutinin (PHA) in primary human mononuclear cells 14,15 . In contrast, other studies have demonstrated that hypoxia skews the pro-inflammatory character (M1-like) of macrophages towards an anti-inflammatory M2-like phenotype 16,17 . In addition to these contradictory findings, these in vitro studies are difficult to interpret, as the control condition is usually room air, which has a higher PaO 2 compared to physiologic tissue PaO 2 .…”