GTS-21, an α7nAChR agonist, increases pulmonary bacterial clearance in mice by restoring hyperoxia-compromised macrophage function

Molecular Medicine

Michelle Zur¹  Ravikumar A. Sitapara¹  Vivek S. Patel¹  Charles R. Ashby¹  Mosi Lin¹  Alex G. Gauthier¹  Lin L. Mantell² 

[1] Department of Pharmaceutical Sciences, St. John’s University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, 11439, Queens, NY, USA;Department of Pharmaceutical Sciences, St. John’s University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, 11439, Queens, NY, USA;The Feinstein Institute for Medical Research, Northwell Health System, 11030, Manhasset, NY, USA;

关键词: α7nAChR;    Hyperoxia;    Macrophage function;    HMGB1;    NF-κB;    Acute lung injury;    Pulmonary infection;   

DOI  :  10.1186/s10020-020-00224-9

来源: Springer

【 摘 要 】

BackgroundMechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia.MethodGTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA.ResultsThe systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA.ConclusionsOur results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.

【 授权许可】

CC BY