Pharmacological stimulation of the cholinergic antiinflammatory pathway

Thomas R. Bernik, Steven G. Friedman, Mahendar Ochani, Robert DiRaimo, Luis Ulloa, Huan Yang, Samridhi Sudan, Christopher J. Czura, Svetlana M. Ivanova, Kevin J. Tracey

Research output: Contribution to journalArticlepeer-review

456 Scopus citations

Abstract

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 α-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanyl-hydrazone 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.

Original languageEnglish (US)
Pages (from-to)781-788
Number of pages8
JournalJournal of Experimental Medicine
Volume195
Issue number6
DOIs
StatePublished - Mar 18 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

  • Endotoxin
  • Neuroimmunology
  • Systemic inflammation
  • TNF
  • Vagus nerve

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