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 μg/kg), physostigmine (80 μg/kg), neostigmine (80 μg/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-κB (p ≤ .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, 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.