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Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis *

Huston, Jared M. MD; Gallowitsch-Puerta, Margot MS; Ochani, Mahendar MD; Ochani, Kanta MD; Yuan, Renqi MD; Rosas-Ballina, Mauricio MD; Ashok, Mala MD; Goldstein, Richard S. MD; Chavan, Sangeeta PhD; Pavlov, Valentin A. PhD; Metz, Christine N. PhD; Yang, Huan MD, PhD; Czura, Christopher J. MS; Wang, Haichao PhD; Tracey, Kevin J. MD

Laboratory Investigations

Objective: Electrical vagus nerve stimulation inhibits proinflammatory cytokine production and prevents shock during lethal systemic inflammation through an [alpha]7 nicotinic acetylcholine receptor ([alpha]7nAChR)-dependent pathway to the spleen, termed the cholinergic anti-inflammatory pathway. Pharmacologic [alpha]7nAChR agonists inhibit production of the critical proinflammatory mediator high mobility group box 1 (HMGB1) and rescue mice from lethal polymicrobial sepsis. Here we developed a method of transcutaneous mechanical vagus nerve stimulation and then investigated whether this therapy can protect mice against sepsis lethality.

Design: Prospective, randomized study.

Setting: Institute-based research laboratory.

Subjects: Male BALB/c mice.

Interventions: Mice received lipopolysaccharide to induce lethal endotoxemia or underwent cecal ligation and puncture to induce polymicrobial sepsis. Mice were then randomized to receive electrical, transcutaneous, or sham vagus nerve stimulation and were followed for survival or euthanized at predetermined time points for cytokine analysis.

Measurements and Main Results: Transcutaneous vagus nerve stimulation dose-dependently reduced systemic tumor necrosis factor levels during lethal endotoxemia. Treatment with transcutaneous vagus nerve stimulation inhibited HMGB1 levels and improved survival in mice with polymicrobial sepsis, even when administered 24 hrs after the onset of disease.

Conclusions: Transcutaneous vagus nerve stimulation is an efficacious treatment for mice with lethal endotoxemia or polymicrobial sepsis.

From the Laboratory of Biomedical Science (JMH, MGP, MO, KO, MRB, MA, SC, VAP, HY, CJC, KJT), Susan and Herman Merinoff Center for Patient Oriented Research (RSG, KJT), and Laboratory of Medicinal Biochemistry (CNM), The Feinstein Institute for Medical Research, Manhasset, NY; and the Department of Emergency Medicine (RY, HW), North Shore University Hospital–New York University School of Medicine, Manhasset, NY.

Supported, in part, by grant M01-RR018535 from the General Clinical Research Center of the Feinstein Institute for Medical Research, by grant RO1GM057226 from the National Institute of General Medical Sciences, and by the Defense Advanced Research Projects Agency.

Drs. Tracey, Pavlov, and Huston and Mr. Czura are inventors on patents related to vagus nerve stimulation and cholinergic agonists as anti-inflammatory agents. Dr. Tracey is a cofounder and consultant to Critical Therapeutics, Boston, MA. Dr. Tracey has consulted for and owns stock in Innovative Metabolics, Boston, MA.

Address requests for reprints to: Kevin J. Tracey, MD, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030. E-mail:

*See also p. 2868.

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