P-145 - Hyperoxia-induced macrophage dysfunction and acute lung injury are attenuated by modulation of α7nAChR via reduced HMGB1 hyperacetylation and release

Abstract

Prolonged exposure to hyperoxia during mechanical ventilation (MV) can result in acute lung injury (ALI) and is associated with HMGB1 accumulation in the airways. The aim of this study was to determine whether modulation of α7 nicotinic acetylcholine receptor (α7nAChR) with either GTS-21 (partial agonist) or GAT107 (ago-PAM) could inhibit hyperoxia-induced HMGB1 accumulation in the airways and improve innate immunity and clinical outcomes. RAW 264.7 cells, treated with either GTS-21 or GAT107 in the presence of 95% O2 exhibited decreased levels of HMGB1 in culture media and enhanced phagocytic ability. Hyperacetylation of nuclear HMGB1 can lead to its release into the extracellular milieu and is observed in cells exposed to hyperoxia. Activation of α7nAChR is effective in reducing both hyperoxia-induced HMGB1 accumulation and hyperacetylation. To determine whether activation of α7nAChR-mediated macrophage function can be translated into clinical outcomes, mice were exposed to >99% O2 for 3 d with GTS-21 treatment. GTS-21 significantly decreased both the accumulation of airway levels and hyperacetylation of HMGB1, protein content and neutrophil infiltration. Therefore, α7nAChRs represent a possible pharmacological target for the treatment of HALI in patients receiving MV.