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

Alex G Gauthier,Ravikumar Sitapara,Lin L Mantell,Ganesh A Thakur,Charles R Ashby,Edward E Schmidt,Mosi Lin,Abhijit Kulkarni,Jeanette C Perron,Jiaqi Wu

doi:10.3390/antiox10010135

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.

Highlights

Mice exposed to hyperoxic conditions had a significantly higher number of bacterial counts in the lung tissue homogenate (7.68 ± 0.07 log colony-forming units (CFUs)/mL, Figure 1B, p < 0.0001) compared to mice that remained at 21% O2 (3.62 ± 0.35 log CFUs/mL in lung tissue homogenate)
This study demonstrates that GAT107 activates α7 nicotinic acetylcholine receptor (α7nAChR)-dependent pathways within the neuromodulated cholinergic anti-inflammatory system and GAT107 attenuated oxidative stress by increasing the antioxidant response
These results suggest that GAT107 increases bacterial clearance by increasing the phagocytic function of macrophages exposed to hyperoxia by increasing macrophage redox

Summary

Introduction

Oxygen therapy, using concentrations of supplemental oxygen up to 100% (hyperoxia), is a routine treatment for intensive care units (ICU) patients, surgical patients, preterm neonates, patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), requiring home oxygen therapy, and in patients receiving supportive care for airway-associated infections, such as the novel COVID-19 coronavirus [1,2,3,4,5]. Oxygen therapy is a life-saving intervention, prolonged exposure to hyperoxia can compromise lung host defense and cause acute lung injury, due to excessive inflammation (ALI) [6,7]. Patients with compromised host defenses that experience hyperoxia have a higher susceptibility to developing pulmonary bacterial infections that cause. Antioxidants 2021, 10, 135 ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) [8,9]. One-third of all mechanically-ventilated (MV) ICU patients develop VAP, which has a 4.6% mortality rate [10,11,12]

Methods

Results

Discussion

Conclusion