Fig. 6

Hypothesized pathway of GTS-21 inhibited hyperoxia-induced HMGB1 release and improved hyperoxia-compromised macrophage function in bacterial clearance. Under room air conditions, alveolar macrophages (AMs) maintain normal phagocytic activity and efficiently clear bacteria. When macrophages are exposed to hyperoxia, NF-κB p65 subunit is translocated into the nucleus, whereas HMGB1 translocates from the nucleus into the cytoplasm and subsequently into the extracellular milieu, decreasing phagocytosis and bacterial clearance by macrophages. GTS-21 significantly attenuates hyperoxia-impaired bacterial clearance by binding to α7nAChR and suppressing HMGB1 translocation into the cytoplasm and release, which subsequently decreases the accumulation of extracellular HMGB1. GTS-21 also inhibits NF-κB p65 subunit translocation into the nucleus, which may prevent HMGB1 translocation and subsequent release into the extracellular milieu