Pharmacologic cholinesterase inhibition improves survival in experimental sepsis

Objective: Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo. Design: Prospective, randomized laboratory investigation that used an established murine sepsis model. Setting: Research laboratory in a university hospital. Subjects: Female C57BL/6 mice. Interventions: Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 mu g/kg), physostigmine (80 mu g/kg), neostigmine (80 mu g/kg), or solvent three times daily for 3 days. Measurements and Main Results: Treatment with physostigmine significantly reduced lethality (p <= .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p <= .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappa B (p <= .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha., interleukin-1 beta, and interleukin-6 (p <= .001), and pulmonary neutrophil invasion (p <= .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals. Conclusions: Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use.