• Ida A J Giebelen, David J van Westerloo, Gregory J LaRosa, Alex F de Vos, and Tom van der Poll.
• Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. i.a.gieberlen@amc.uva.nl
• Shock. 2007 Dec 1;28(6):700-3.

AbstractThe cholinergic nervous system can inhibit the release of proinflammatory cytokines such as TNF-alpha from LPS-stimulated macrophages. Acetylcholine, the principal neurotransmitter of the vagus nerve, is the key mediator of this so-called cholinergic anti-inflammatory pathway, specifically interacting with alpha7 cholinergic receptors expressed by macrophages and other cell types to inhibit TNF-alpha production. The aim of the current study was to determine the capacity of the selective alpha7 cholinergic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21), administered locally into the airways, to inhibit LPS-induced inflammatory responses in the mouse lung in vivo. GTS-21 dose-dependently inhibited LPS-induced TNF-alpha release by MH-S mouse alveolar macrophages in vitro. Intranasal inoculation with GTS-21 also dose-dependently inhibited TNF-alpha release into the lung compartment after intrapulmonary delivery of LPS in mice in vivo, whereas IL-6 concentrations were not affected. However, GTS-21 did not influence the influx of neutrophils into bronchoalveolar lavage fluid elicited by LPS and increased the concentrations of the neutrophil-attracting chemokines cytokine-induced neutrophil chemoattractant and macrophage inflammatory protein 2. These data indicate that local administration of GTS-21 inhibits TNF-alpha release in the lung during LPS-induced inflammation.

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