Severe sepsis, a leading cause of death in hospitalized patients, is one of the most dramatic examples of the pathological potential of
inflammation. Since
inflammation contributes to multiple clinical scenarios, it may not be surprising that diverse infectious and inflammatory disorders converge in the pathogenesis of
severe sepsis. The physiological regulation of the immune responses by the nervous system represents effective anti-inflammatory mechanisms that can be exploited against inflammatory disorders. Recent studies indicate that
acetylcholine, the principal
cholinergic neurotransmitter, also functions as an immune
cytokine that prevents macrophage activation through a 'nicotinic anti-inflammatory pathway'.
Nicotine is more efficient than
acetylcholine at inhibiting the
NF-kappaB pathway and attenuating the production of pro-inflammatory
cytokines from macrophages through a mechanism dependent on the alpha7-nicotinic
acetylcholine receptor (alpha7n AChR). Treatment with
nicotinic agonists attenuated systemic
inflammation and improved survival in experimental
sepsis in a clinically relevant time frame.
Nicotine has already been used in clinical trials, but its clinical potential is limited by its collateral toxicity. Similar to the development of selective agonists for
adrenergic receptors, selective
nicotinic agonists for the
alpha7nAChR may represent a promising pharmacological strategy against infectious and inflammatory diseases.