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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.
Afiliação
  • 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 em En | MEDLINE | ID: mdl-32600307
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridinas / Compostos de Benzilideno / Agonistas Nicotínicos / Hiperóxia / Proteína HMGB1 / Lesão Pulmonar Aguda Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridinas / Compostos de Benzilideno / Agonistas Nicotínicos / Hiperóxia / Proteína HMGB1 / Lesão Pulmonar Aguda Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article