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The α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuates hyperoxia-induced acute inflammatory lung injury by alleviating the accumulation of HMGB1 in the airways and the circulation.
Sitapara, Ravikumar A; Gauthier, Alex G; Valdés-Ferrer, Sergio I; Lin, Mosi; Patel, Vivek; Wang, Mao; Martino, Ashley T; Perron, Jeanette C; Ashby, Charles R; Tracey, Kevin J; Pavlov, Valentin A; Mantell, Lin L.
  • Sitapara RA; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Gauthier AG; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Valdés-Ferrer SI; Feinstein Institutes for Medical Research, Northwell Health System, 350 Community Drive, Manhasset, New York, 11030, USA.
  • Lin M; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Patel V; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Wang M; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Martino AT; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Perron JC; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Ashby CR; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA.
  • Tracey KJ; Feinstein Institutes for Medical Research, Northwell Health System, 350 Community Drive, Manhasset, New York, 11030, USA.
  • Pavlov VA; Feinstein Institutes for Medical Research, Northwell Health System, 350 Community Drive, Manhasset, New York, 11030, USA. vpavlov@northwell.edu.
  • Mantell LL; Department of Pharmaceutical Sciences, St, College of Pharmacy and Health Sciences, St. John's University College of Pharmacy and Health Sciences, St. Albert Hall, 8000 Utopia Parkway, Queens, New York, 11439, USA. mantelll@stjohns.edu.
Mol Med ; 26(1): 63, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-617382
Semantic information from SemMedBD (by NLM)
1. GTS-21 CAUSES Accumulation
Subject
GTS-21
Predicate
CAUSES
Object
Accumulation
2. Airway structure LOCATION_OF HMGB1 Protein
Subject
Airway structure
Predicate
LOCATION_OF
Object
HMGB1 Protein
3. Warburg Therapy USES oxygen
Subject
Warburg Therapy
Predicate
USES
Object
oxygen
4. HMGB1 Protein ADMINISTERED_TO Patients
Subject
HMGB1 Protein
Predicate
ADMINISTERED_TO
Object
Patients
5. HMGB1 Protein ASSOCIATED_WITH Lung Injury
Subject
HMGB1 Protein
Predicate
ASSOCIATED_WITH
Object
Lung Injury
6. Lung Injury COEXISTS_WITH Mouse Model
Subject
Lung Injury
Predicate
COEXISTS_WITH
Object
Mouse Model
7. alpha7 Nicotinic Acetylcholine Receptor AFFECTS Inflammatory disorder
Subject
alpha7 Nicotinic Acetylcholine Receptor
Predicate
AFFECTS
Object
Inflammatory disorder
8. Airway structure LOCATION_OF Accumulation
Subject
Airway structure
Predicate
LOCATION_OF
Object
Accumulation
9. GTS-21 INHIBITS Accumulation
Subject
GTS-21
Predicate
INHIBITS
Object
Accumulation
10. anabaseine dihydrochloride TREATS Lung Injury
Subject
anabaseine dihydrochloride
Predicate
TREATS
Object
Lung Injury
11. Serum LOCATION_OF HMGB1 Protein
Subject
Serum
Predicate
LOCATION_OF
Object
HMGB1 Protein
12. GTS-21 INHIBITS HMGB1 Protein
Subject
GTS-21
Predicate
INHIBITS
Object
HMGB1 Protein
13. GTS-21 CAUSES Decreased total protein
Subject
GTS-21
Predicate
CAUSES
Object
Decreased total protein
14. Airway structure LOCATION_OF Decreased total protein
Subject
Airway structure
Predicate
LOCATION_OF
Object
Decreased total protein
15. HMGB1 Protein PART_OF Extracellular
Subject
HMGB1 Protein
Predicate
PART_OF
Object
Extracellular
16. GTS-21 TREATS Acute Lung Injury
Subject
GTS-21
Predicate
TREATS
Object
Acute Lung Injury
17. Warburg Therapy ADMINISTERED_TO Patients
Subject
Warburg Therapy
Predicate
ADMINISTERED_TO
Object
Patients
18. Treatment Protocols TREATS Patients
Subject
Treatment Protocols
Predicate
TREATS
Object
Patients
19. GTS-21 CAUSES Accumulation
Subject
GTS-21
Predicate
CAUSES
Object
Accumulation
20. Airway structure LOCATION_OF HMGB1 Protein
Subject
Airway structure
Predicate
LOCATION_OF
Object
HMGB1 Protein
21. Warburg Therapy USES oxygen
Subject
Warburg Therapy
Predicate
USES
Object
oxygen
22. HMGB1 Protein ADMINISTERED_TO Patients
Subject
HMGB1 Protein
Predicate
ADMINISTERED_TO
Object
Patients
23. HMGB1 Protein ASSOCIATED_WITH Lung Injury
Subject
HMGB1 Protein
Predicate
ASSOCIATED_WITH
Object
Lung Injury
24. Lung Injury COEXISTS_WITH Mouse Model
Subject
Lung Injury
Predicate
COEXISTS_WITH
Object
Mouse Model
25. alpha7 Nicotinic Acetylcholine Receptor AFFECTS Inflammatory disorder
Subject
alpha7 Nicotinic Acetylcholine Receptor
Predicate
AFFECTS
Object
Inflammatory disorder
26. Airway structure LOCATION_OF Accumulation
Subject
Airway structure
Predicate
LOCATION_OF
Object
Accumulation
27. GTS-21 INHIBITS Accumulation
Subject
GTS-21
Predicate
INHIBITS
Object
Accumulation
28. anabaseine dihydrochloride TREATS Lung Injury
Subject
anabaseine dihydrochloride
Predicate
TREATS
Object
Lung Injury
29. Serum LOCATION_OF HMGB1 Protein
Subject
Serum
Predicate
LOCATION_OF
Object
HMGB1 Protein
30. GTS-21 INHIBITS HMGB1 Protein
Subject
GTS-21
Predicate
INHIBITS
Object
HMGB1 Protein
31. GTS-21 CAUSES Decreased total protein
Subject
GTS-21
Predicate
CAUSES
Object
Decreased total protein
32. Airway structure LOCATION_OF Decreased total protein
Subject
Airway structure
Predicate
LOCATION_OF
Object
Decreased total protein
33. HMGB1 Protein PART_OF Extracellular
Subject
HMGB1 Protein
Predicate
PART_OF
Object
Extracellular
34. GTS-21 TREATS Acute Lung Injury
Subject
GTS-21
Predicate
TREATS
Object
Acute Lung Injury
35. Warburg Therapy ADMINISTERED_TO Patients
Subject
Warburg Therapy
Predicate
ADMINISTERED_TO
Object
Patients
36. Treatment Protocols TREATS Patients
Subject
Treatment Protocols
Predicate
TREATS
Object
Patients
ABSTRACT

BACKGROUND:

Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury.

METHODS:

Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline.

RESULTS:

The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology.

CONCLUSIONS:

Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Pyridines / Benzylidene Compounds / Nicotinic Agonists / Hyperoxia / HMGB1 Protein / Acute Lung Injury Topics: Long Covid Limits: Animals Language: English Journal: Mol Med Journal subject: Molecular Biology Year: 2020 Document Type: Article Affiliation country: S10020-020-00177-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pyridines / Benzylidene Compounds / Nicotinic Agonists / Hyperoxia / HMGB1 Protein / Acute Lung Injury Topics: Long Covid Limits: Animals Language: English Journal: Mol Med Journal subject: Molecular Biology Year: 2020 Document Type: Article Affiliation country: S10020-020-00177-z