GAT107-mediated?7 nicotinic acetylcholine receptor signaling attenuates inflammatory lung injury and mortality in a mouse model of ventilator-associated pneumonia by alleviating macrophage mitochondrial oxidative stress via reducing MnSOD-S-glutathionylation

Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase suscepti-bility to bacterial and viral infections, causing ventilator-associated pneumonia (VAP). Compromised host de-fense and inflammatory lung injury are mediated, in part, by high extracellular concentrations of HMGB1, which can be decreased by GTS-21, a partial agonist of alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR). Here, we report that a novel alpha 7nAChR agonistic positive allosteric modulator (ago-PAM), GAT107, at 3.3 mg/kg, i.p., signifi-cantly decreased animal mortality and markers of inflammatory injury in mice exposed to hyperoxia and sub-sequently infected with Pseudomonas aeruginosa. The incubation of macrophages with 3.3 mu M of GAT107 significantly decreased hyperoxia-induced extracellular HMGB1 accumulation and HMGB1-induced macrophage phagocytic dysfunction. Hyperoxia-compromised macrophage function was correlated with impaired mito-chondrial membrane integrity, increased superoxide levels, and decreased manganese superoxide dismutase (MnSOD) activity. This compromised MnSOD activity is due to a significant increase in its level of gluta-thionylation. The incubation of hyperoxic macrophages with 3.3 mu M of GAT107 significantly decreases the levels of glutathionylated MnSOD, and restores MnSOD activity and mitochondrial membrane integrity. Thus, GAT107 restored hyperoxia-compromised phagocytic functions by decreasing HMGB1 release, most likely via a mitochondrial-directed pathway. Overall, our results suggest that GAT107 may be a potential treatment to decrease acute inflammatory lung injury by increasing host defense in patients with VAP.

Automated summary

Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial and viral infections, causing ventilator-associated pneumonia (VAP). GAT107, a novel alpha 7nAChR agonistic positive allosteric modulator, significantly decreased animal mortality and markers of inflammatory injury in mice exposed to hyperoxia and subsequently infected with Pseudomonas aeruginosa. GAT107 restored hyperoxia-compromised phagocytic functions by decreasing HMGB1 release, most likely via a mitochondrial-directed pathway, suggesting it as a potential treatment for acute inflammatory lung injury.