Supplemental
oxygen therapy with supraphysiological concentrations of
oxygen (
hyperoxia; >21% O2) is a life-saving intervention for patients experiencing respiratory distress. However, prolonged exposure to
hyperoxia can compromise bacterial clearance processes, due to oxidative stress-mediated impairment of macrophages, contributing to the increased susceptibility to pulmonary
infections. This study reports that the activation of the α7
nicotinic acetylcholine receptor (α7nAChR) with the delete allosteric agonistic-positive allosteric modulator,
GAT107, decreases the bacterial burden in mouse lungs by improving
hyperoxia-induced lung redox imbalance. The incubation of RAW 264.7 cells with
GAT107 (3.3 µM) rescues
hyperoxia-compromised phagocytic functions in cultured macrophages, RAW 264.7 cells, and primary bone marrow-derived macrophages. Similarly,
GAT107 (3.3 µM) also attenuated oxidative stress in
hyperoxia-exposed macrophages, which prevents oxidation and hyper-polymerization of phagosome filamentous actin (
F-actin) from oxidation. Furthermore,
GAT107 (3.3 µM) increases the (1) activity of
superoxide dismutase 1; (2) activation of Nrf2 and (3) the expression of
heme oxygenase-1 (HO-1) in macrophages exposed to
hyperoxia. Overall, these data suggest that the novel α7nAChR compound,
GAT107, could be used to improve host defense functions in patients, such as those with
COVID-19, who are exposed to prolonged periods of
hyperoxia.