alpha 7 Nicotinic Acetylcholine Receptor Agonists Regulate Inflammation and Growth Hormone Resistance in Sepsis

During sepsis the normal induction of circulating insulin-like growth factor-I (IGF-I) by growth hormone (GH) action on liver is attenuated, a phenomenon called hepatic GH resistance. Hepatic GH resistance can be caused by cytokine-mediated activation of the NF-kappa B pathway which interferes with normal GH-signaling. The afferent and efferent fibers of the vagus nerve are integral to the cholinergic anti-inflammatory pathway (CAP) which attenuates hepatic TNF alpha production by activating the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR). We examined the effects of selective afferent vagotomy (SAV) and alpha 7nAChR activation on sepsis-induced mortality, hepatic and systemic inflammation, the GH/IGF system and hepatic GH resistance using Sprague Dawley (SD) rats, C57BL/6 wild type (WT) mice, and alpha 7nAChR knockout (KO) mice. Capsaicin was used to perform SAV and GTS-21 (alpha 7nAChR agonist) was used to activate the alpha 7nAChR. Sepsis-induced mortality, hepatic NF-kappa B activation, and plasma cytokine levels were increased in SAV rats and reduced in GTS-21-treated mice. The effects of sepsis on the GH/IGF-I system plasma IGF-I, IGF binding protein-1 (IGFBP-1), hepatic IGF-I, IGFBP-1, and GH receptor (GHR) mRNA and rhGH-responsiveness in mice were improved by GTS-21. Collectively these results confirm the protective effects of the anti-inflammatory CAP and alpha 7nAChR activation in sepsis. They also provide evidence the CAP and alpha 7nAChR activation could be used to attenuate hepatic GH resistance and anabolic failure in sepsis.