Pharmacological stimulation of the cholinergic antiinflammatory pathway.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Bernik, TR; Friedman, SG; Ochani, M; DiRaimo, R; Ulloa, L; Yang, H; Sudan, S; Czura, CJ; Ivanova, SM; Tracey, KJ
Published Date
- March 18, 2002
Published In
Volume / Issue
- 195 / 6
Start / End Page
- 781 - 788
PubMed ID
- 11901203
Pubmed Central ID
- 11901203
International Standard Serial Number (ISSN)
- 0022-1007
Digital Object Identifier (DOI)
- 10.1084/jem.20011714
Language
- eng
Conference Location
- United States