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.

中文翻译：

---

GAT107 对 α7-烟碱胆碱能受体的正变构调节通过降低巨噬细胞的氧化应激来增加高氧小鼠的细菌肺清除率


使用超生理浓度的氧气（高氧；>21% O ₂ ）进行补充氧疗对于经历呼吸窘迫的患者来说是一种挽救生命的干预措施。然而，由于氧化应激介导的巨噬细胞损伤，长时间暴露在高氧环境中会损害细菌清除过程，从而导致肺部感染的易感性增加。这项研究报告称，用删除变构激动阳性变构调节剂 GAT107 激活 α7 烟碱乙酰胆碱受体 (α7nAChR)，可通过改善高氧诱导的肺氧化还原失衡来减少小鼠肺部的细菌负荷。将 RAW 264.7 细胞与 GAT107 (3.3 µM) 一起孵育可挽救培养的巨噬细胞、RAW 264.7 细胞和原代骨髓源性巨噬细胞中因高氧受损的吞噬功能。同样，GAT107 (3.3 µM) 还可减轻高氧暴露巨噬细胞中的氧化应激，从而防止吞噬体丝状肌动蛋白 (F-肌动蛋白) 氧化和过度聚合。此外，GAT107 (3.3 µM) 会增加 (1) 超氧化物歧化酶 1 的活性； (2) Nrf2 的激活和 (3) 暴露于高氧的巨噬细胞中血红素加氧酶-1 (HO-1) 的表达。总体而言，这些数据表明新型 α7nAChR 化合物 GAT107 可用于改善患者的宿主防御功能，例如那些长期处于高氧状态的 COVID-19 患者。