title: α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-α production and lung injury.
abstract: BACKGROUND
  Mechanical ventilation (MV) induces an inflammatory response that can lead to lung injury. The vagus nerve can limit the inflammatory response through the cholinergic anti-inflammatory pathway. We evaluated the effects of stimulation of the cholinergic anti-inflammatory pathway with the selective partial α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 on inflammation and lung injury induced by MV using clinically relevant ventilator settings. Furthermore, we investigated whether altering endogenous cholinergic signalling, by administration of the non-specific nAChR antagonist mecamylamine and the peripherally acting acetylcholinesterase inhibitor neostigmine, modulates the MV-induced inflammatory response.
  
  
  METHODS
  C57BL6 mice were injected i.p. with either the selective α7nAChR agonist GTS-21 (8 mg kg(-1)), the acetylcholinesterase inhibitor neostigmine (80 μg kg(-1)), the nAChR antagonist mecamylamine (1 mg kg(-1)), or a placebo; followed by 4 h of MV (8 ml kg(-1), 1.5 cm H(2)O PEEP).
  
  
  RESULTS
  MV resulted in release of cytokines in plasma and lungs compared with unventilated mice. Lung and plasma levels of tumour necrosis factor (TNF)-α, but not of interleukin-10, were lower in GTS-21-treated animals compared with placebo (P<0.05). In addition, GTS-21 lowered the alveolar-arterial gradient, indicating improved lung function (P=0.04). Neither neostigmine nor mecamylamine had an effect on MV-induced inflammation or lung function.
  
  
  CONCLUSIONS
  MV with clinically relevant ventilator settings results in pulmonary and systemic inflammation. Stimulation of the cholinergic anti-inflammatory pathway with GTS-21 attenuates MV-induced release of TNF-α, which was associated with reduced lung injury. Modulation of endogenous cholinergic signalling did not affect the MV-induced inflammatory response. Selective stimulation of the cholinergic anti-inflammatory pathway may represent new treatment options for MV-induced lung injury.
authors.affiliation: Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands. m.kox@ic.umcn.nl
authors.forename: M
authors.initials: M
authors.lastname: Kox
authors.forename: J C
authors.initials: JC
authors.lastname: Pompe
authors.forename: E
authors.initials: E
authors.lastname: Peters
authors.forename: M
authors.initials: M
authors.lastname: Vaneker
authors.forename: J W
authors.initials: JW
authors.lastname: van der Laak
authors.forename: J G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: G J
authors.initials: GJ
authors.lastname: Scheffer
authors.forename: C W
authors.initials: CW
authors.lastname: Hoedemaekers
authors.forename: P
authors.initials: P
authors.lastname: Pickkers
mesh_terms: D055371:Acute Lung Injury / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009388:Neostigmine / Q000494:pharmacology; D020556:Neutrophil Infiltration; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011014:Pneumonia / Q000473:pathology / Q000517:prevention & control; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012121:Respiration, Artificial / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D055397:Ventilator-Induced Lung Injury / Q000473:pathology / Q000517:prevention & control*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001597:Benzylidene Compounds; D002800:Cholinesterase Inhibitors; C579166:Chrna7 protein, mouse; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016753:Interleukin-10; D009388:Neostigmine; D008464:Mecamylamine; C088936:3-(2,4-dimethoxybenzylidene)anabaseine