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The α7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function.
Sitapara, Ravikumar A; Gauthier, Alex G; Patel, Vivek S; Lin, Mosi; Zur, Michelle; Ashby, Charles R; Mantell, Lin L.
  • Sitapara RA; Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA.
  • Gauthier AG; Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA.
  • Patel VS; Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA.
  • Lin M; Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA.
  • Zur M; Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA.
  • Ashby CR; Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA.
  • Mantell LL; Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY, 11439, USA. mantelll@stjohns.edu.
Mol Med ; 26(1): 98, 2020 10 30.
Article in English | MEDLINE | ID: covidwho-894987
Semantic information from SemMedBD (by NLM)
1. GTS-21 TREATS Mus
Subject
GTS-21
Predicate
TREATS
Object
Mus
2. oxygen TREATS Respiratory distress
Subject
oxygen
Predicate
TREATS
Object
Respiratory distress
3. Respiratory distress PROCESS_OF Patients
Subject
Respiratory distress
Predicate
PROCESS_OF
Object
Patients
4. oxygen TREATS Patients
Subject
oxygen
Predicate
TREATS
Object
Patients
5. macrophage LOCATION_OF Phagocytosis
Subject
macrophage
Predicate
LOCATION_OF
Object
Phagocytosis
6. HMGB1 Protein PART_OF Nuclear Proteins
Subject
HMGB1 Protein
Predicate
PART_OF
Object
Nuclear Proteins
7. Airway structure PART_OF Lung
Subject
Airway structure
Predicate
PART_OF
Object
Lung
8. Hyperoxia CAUSES Patient Discharge
Subject
Hyperoxia
Predicate
CAUSES
Object
Patient Discharge
9. HMGB1 Protein PART_OF Extracellular
Subject
HMGB1 Protein
Predicate
PART_OF
Object
Extracellular
10. HMGB1 Protein DISRUPTS Phagocytosis
Subject
HMGB1 Protein
Predicate
DISRUPTS
Object
Phagocytosis
11. Phagocytosis PROCESS_OF Mouse Model
Subject
Phagocytosis
Predicate
PROCESS_OF
Object
Mouse Model
12. Injection USES C0258259
Subject
Injection
Predicate
USES
Object
C0258259
13. GTS-21 PREVENTS Acute Lung Injury
Subject
GTS-21
Predicate
PREVENTS
Object
Acute Lung Injury
14. GTS-21 TREATS Present
Subject
GTS-21
Predicate
TREATS
Object
Present
15. macrophage LOCATION_OF positive regulation of NF-kappaB transcription factor activity
Subject
macrophage
Predicate
LOCATION_OF
Object
positive regulation of NF-kappaB transcription factor activity
16. RAW 264.7 Cells LOCATION_OF HMGB1 Protein
Subject
RAW 264.7 Cells
Predicate
LOCATION_OF
Object
HMGB1 Protein
17. HMGB1 Protein INTERACTS_WITH Pseudomonas aeruginosa
Subject
HMGB1 Protein
Predicate
INTERACTS_WITH
Object
Pseudomonas aeruginosa
18. GTS-21 TREATS Mus
Subject
GTS-21
Predicate
TREATS
Object
Mus
19. oxygen TREATS Respiratory distress
Subject
oxygen
Predicate
TREATS
Object
Respiratory distress
20. Respiratory distress PROCESS_OF Patients
Subject
Respiratory distress
Predicate
PROCESS_OF
Object
Patients
21. oxygen TREATS Patients
Subject
oxygen
Predicate
TREATS
Object
Patients
22. macrophage LOCATION_OF Phagocytosis
Subject
macrophage
Predicate
LOCATION_OF
Object
Phagocytosis
23. HMGB1 Protein PART_OF Nuclear Proteins
Subject
HMGB1 Protein
Predicate
PART_OF
Object
Nuclear Proteins
24. Airway structure PART_OF Lung
Subject
Airway structure
Predicate
PART_OF
Object
Lung
25. Hyperoxia CAUSES Patient Discharge
Subject
Hyperoxia
Predicate
CAUSES
Object
Patient Discharge
26. HMGB1 Protein PART_OF Extracellular
Subject
HMGB1 Protein
Predicate
PART_OF
Object
Extracellular
27. HMGB1 Protein DISRUPTS Phagocytosis
Subject
HMGB1 Protein
Predicate
DISRUPTS
Object
Phagocytosis
28. Phagocytosis PROCESS_OF Mouse Model
Subject
Phagocytosis
Predicate
PROCESS_OF
Object
Mouse Model
29. Injections, Intraperitoneal USES GTS-21
Subject
Injections, Intraperitoneal
Predicate
USES
Object
GTS-21
30. GTS-21 PREVENTS Acute Lung Injury
Subject
GTS-21
Predicate
PREVENTS
Object
Acute Lung Injury
31. GTS-21 TREATS Present
Subject
GTS-21
Predicate
TREATS
Object
Present
32. macrophage LOCATION_OF positive regulation of NF-kappaB transcription factor activity
Subject
macrophage
Predicate
LOCATION_OF
Object
positive regulation of NF-kappaB transcription factor activity
33. RAW 264.7 Cells LOCATION_OF HMGB1 Protein
Subject
RAW 264.7 Cells
Predicate
LOCATION_OF
Object
HMGB1 Protein
34. HMGB1 Protein INTERACTS_WITH Pseudomonas aeruginosa
Subject
HMGB1 Protein
Predicate
INTERACTS_WITH
Object
Pseudomonas aeruginosa
ABSTRACT

BACKGROUND:

Mechanical 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.

METHOD:

GTS-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.

RESULTS:

The 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.

CONCLUSIONS:

Our 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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Pseudomonas Infections / Pyridines / Benzylidene Compounds / Macrophages, Alveolar / Hyperoxia / Ventilator-Induced Lung Injury / Alpha7 Nicotinic Acetylcholine Receptor Limits: Animals Language: English Journal: Mol Med Journal subject: Molecular Biology Year: 2020 Document Type: Article Affiliation country: S10020-020-00224-9

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pseudomonas Infections / Pyridines / Benzylidene Compounds / Macrophages, Alveolar / Hyperoxia / Ventilator-Induced Lung Injury / Alpha7 Nicotinic Acetylcholine Receptor Limits: Animals Language: English Journal: Mol Med Journal subject: Molecular Biology Year: 2020 Document Type: Article Affiliation country: S10020-020-00224-9