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 microg/kg), physostigmine (80 microg/kg), neostigmine (80 microg/kg), or solvent three times daily for 3 days. MEASUREMENTS AND MAIN RESULTS: Treatment with physostigmine significantly reduced lethality (p < or = .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p < or = .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappaB (p < or = .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (p < or = .001), and pulmonary neutrophil invasion (p < or = .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.
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 murinesepsis 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 microg/kg), physostigmine (80 microg/kg), neostigmine (80 microg/kg), or solvent three times daily for 3 days. MEASUREMENTS AND MAIN RESULTS: Treatment with physostigmine significantly reduced lethality (p < or = .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p < or = .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappaB (p < or = .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (p < or = .001), and pulmonary neutrophil invasion (p < or = .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.
Authors: Sherri C Young; Karine M Fabio; Mou-Tuan Huang; Jaya Saxena; Meredith P Harman; Christophe D Guillon; Anna M Vetrano; Diane E Heck; Robert A Flowers; Ned D Heindel; Jeffrey D Laskin Journal: J Appl Toxicol Date: 2011-02-11 Impact factor: 3.446