alpha7 Nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-alpha production and lung injury,α7 Nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-alpha production and lung injury

Item does not contain fulltextBACKGROUND: 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