a7 Nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-a production and lung injury

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 antiinflammatory pathway with the selective partial a7 nicotinic acetylcholine receptor (a7nAChR) 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-speci?c 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 a7nAChR agonist GTS-21 (8 mg kg21), the acetylcholinesterase inhibitor neostigmine (80 mg kg21), the nAChR antagonist mecamylamine (1 mg kg21), or a placebo; followed by 4 h of MV (8 ml kg21, 1.5 cm H2O 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)-a, 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 1/4 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-a, 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.