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

M. Kox, J. Pompe, E. Peters, V. M., J. van der Laak, J. van der Hoeven, G. Scheffer, C. Hoedemaekers and P. Pickkers

British Journal of Anaesthesia (2011)

DOI

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 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 (P¼0.04). 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.

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