The Journal of Experimental Medicine
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Published 18 March 2002. doi:10.1084/jem.20011714
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© Rockefeller University Press, 0022-1007/2002/3/781/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 6, March 18, 2002 781-788

Article

Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway

Thomas R. Bernik1,2, Steven G. Friedman1,2, Mahendar Ochani1, Robert DiRaimo1,2, Luis Ulloa1, Huan Yang1, Samridhi Sudan1, Christopher J. Czura1, Svetlana M. Ivanova1 and Kevin J. Tracey1

1 Laboratory of Biomedical Science, North Shore-LIJ Research Institute
2 Department of Vascular Surgery, North Shore University Hospital, Manhasset, NY 11030

Address correspondence to Kevin J. Tracey, FACS Laboratory of Biomedical Science North Shore-LIJ Research Institute, 350 Community Dr., Manhasset, NY 11030. Phone: 516-562-2813; Fax: 516-562-2356; E-mail: kjtracey{at}sprynet.com

Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the "cholinergic antiinflammatory pathway," inhibition of TNF synthesis is dependent on nicotinic {alpha}-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock.

Key Words: vagus nerve • endotoxin • TNF • systemic inflammation • neuroimmunology


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