alpha7 Nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-alpha production and lung injury
Publication year
2011Source
British Journal of Anaesthesia, 107, 4, (2011), pp. 559-66ISSN
Publication type
Article / Letter to editor
![https://hdl.handle.net/2066/98553](https://cdn.statically.io/img/repository.ubn.ru.nl/themes/Mirage2//images/copy.png)
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Organization
Anesthesiology
Intensive Care
Geriatrics
Pathology
Journal title
British Journal of Anaesthesia
Volume
vol. 107
Issue
iss. 4
Page start
p. 559
Page end
p. 66
Subject
DCN 1: Perception and Action N4i 4: Auto-immunity, transplantation and immunotherapy; IGMD 7: Iron metabolism N4i 1: Pathogenesis and modulation of inflammation; N4i 1: Pathogenesis and modulation of inflammation; N4i 4: Auto-immunity, transplantation and immunotherapy; ONCOL 3: Translational researchAbstract
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 alpha7 nicotinic acetylcholine receptor (alpha7nAChR) 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 alpha7nAChR agonist GTS-21 (8 mg kg(-1)), the acetylcholinesterase inhibitor neostigmine (80 mug 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)-alpha, 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-alpha, 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.
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- Faculty of Medical Sciences [91954]
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