The Positive Allosteric Modulation of alpha7-Nicotinic Cholinergic Receptors by GAT107 Increases Bacterial Lung Clearance in Hyperoxic Mice by Decreasing Oxidative Stress in Macrophages

Abstract

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.

Dual effects of supplemental oxygen on pulmonary infection, inflammatory lung injury, and neuromodulation in aging and COVID-19

“…The activation of the CAIP can maintain the inflammatory homeostasis to prevent prolonged dysregulated inflammation, which can produce tissues injury, such as ALI/ARDS, systemic inflammation, sepsis, multiple organ failure and death [ 33 , 118 , 119 ]. Numerous studies have shown that activation of the CAIP can significantly tame the overproduction of proinflammatory cytokines and attenuate lung injury in mouse models of ALI/ARDS-induced by hyperoxia, pneumonia or sepsis [ 109 , [120] , [121] , [122] , [123] , [124] ].…”

“…The efficacy of CAIP activation has been reported in animals and patients with inflammatory disorders. For example, the activation of the CAIP by α7nAChRs agonists can inhibit the excessive production of proinflammatory cytokines and improve clinical outcomes in animal models of sepsis and ALI/ARDS [ 109 , 115 , 121 , 123 , 142 ]. Electronic-based interventions, such as vagus nerve stimulation and electro-acupuncture points, can also decrease the levels of both proinflammatory cytokines, such as IL-4, IL-5, IL-6, IL-13, and inflammatory cell infiltration as seen in animal models of inflammatory diseases/disorders, including endotoxemia-induced ALI/sepsis [ [143] , [144] , [145] ].…”

“…As discussed above, functional CAIP is critical for pulmonary integrity and its physiological functions. Thus, the activation of α7nAChR in the CAIP is important, as this can decrease the levels of certain pro-inflammatory cytokines, thereby maintaining inflammatory homeostasis in the lungs [ 109 , 116 , 117 , 121 , 123 , 151 ]. The α7nAChRs are widely expressed in lung cells, and have been identified in airway epithelial cells, alveolar macrophages and epithelial cells [ 152 ], neutrophils [ 152 ], and B- and T-lymphocytes [ 153 , 154 ].…”

“…The α7nAChR can be rapidly desensitized by ACh, whereas in vitro, the combination of GAT107 with ACh produces a significant decrease in the ACh-induced desensitization of the receptor [ 185 , 187 ]. GAT107 (3.3 mg/kg i. p.) can restore the hyperoxia-induced impairment of bacterial clearance in mice by enhancing the phagocytic function of cultured murine macrophages [ 121 ] and increasing the activity and protein levels of the antioxidant enzyme, superoxide dismutase (SOD1). In addition to SOD1, GAT107 also increased the activation of transcription factor Nrf2 and its downstream effector, heme oxygenase-1 in cultured macrophages [ 121 ].…”

“…GAT107 (3.3 mg/kg i. p.) can restore the hyperoxia-induced impairment of bacterial clearance in mice by enhancing the phagocytic function of cultured murine macrophages [ 121 ] and increasing the activity and protein levels of the antioxidant enzyme, superoxide dismutase (SOD1). In addition to SOD1, GAT107 also increased the activation of transcription factor Nrf2 and its downstream effector, heme oxygenase-1 in cultured macrophages [ 121 ]. Thus, α7nAChR agonists can effectively maintain CAIP regulation of macrophage-mediated inflammatory responses and the integrity of the function of the innate immunity under hyperoxic conditions [ 109 , 121 , 123 , 127 ].…”