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)
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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