Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis.
OBJECTIVE
Electrical vagus nerve stimulation inhibits proinflammatory cytokine production and prevents shock during lethal systemic inflammation through an alpha7 nicotinic acetylcholine receptor (alpha7nAChR)-dependent pathway to the spleen, termed the cholinergic anti-inflammatory pathway. Pharmacologic alpha7nAChR 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.


METHODS
Prospective, randomized study.


METHODS
Institute-based research laboratory.


METHODS
Male BALB/c mice.


METHODS
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.


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.
Huston
Jared M
JM
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
Gallowitsch-Puerta
Margot
M
Ochani
Mahendar
M
Ochani
Kanta
K
Yuan
Renqi
R
Rosas-Ballina
Mauricio
M
Ashok
Mala
M
Goldstein
Richard S
RS
Chavan
Sangeeta
S
Pavlov
Valentin A
VA
Metz
Christine N
CN
Yang
Huan
H
Czura
Christopher J
CJ
Wang
Haichao
H
Tracey
Kevin J
KJ
D000818:Animals; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia; D024243:HMGB1 Protein / Q000097:blood*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015213:Neuroimmunomodulation; D011446:Prospective Studies; D011897:Random Allocation; D018805:Sepsis / Q000276:immunology / Q000628:therapy*; D016019:Survival Analysis; D004561:Transcutaneous Electric Nerve Stimulation / Q000379:methods*; D014630:Vagus Nerve
D016207:Cytokines; D024243:HMGB1 Protein