Abstract | BACKGROUND & AIMS: We previously showed that intestinal inflammation is reduced by electrical stimulation of the efferent vagus nerve, which prevents postoperative ileus in mice. We propose that this cholinergic anti-inflammatory pathway is mediated via alpha7 nicotinic acetylcholine receptors expressed on macrophages. The aim of this study was to evaluate pharmacologic activation of the cholinergic anti-inflammatory pathway in a mouse model for postoperative ileus using the alpha7 nicotinic acetylcholine receptor-agonist AR-R17779. METHODS: Mice were pretreated with vehicle, nicotine, or AR-R17779 20 minutes before a laparotomy (L) or intestinal manipulation (IM). Twenty-four hours thereafter gastric emptying was determined using scintigraphy and intestinal muscle inflammation was quantified. Nuclear factor-kappaB transcriptional activity and cytokine production was assayed in peritoneal macrophages. RESULTS: Twenty-four hours after surgery IM led to a delayed gastric emptying compared with L (gastric retention: L(saline) 14% +/- 4% vs IM(saline) 38% +/- 10%, P = .04). Pretreatment with AR-R17779 prevented delayed gastric emptying (IM(AR-R17779) 15% +/- 4%, P = .03). IM elicited inflammatory cell recruitment (L(saline) 50 +/- 8 vs IM(saline) 434 +/- 71 cells/mm(2), P = .001) which was reduced by AR-R17779 pretreatment (IM(AR-R17779) 231 +/- 32 cells/mm(2), P = .04). An equimolar dose of nicotine was not tolerated. Subdiaphragmal vagotomy did not affect the anti-inflammatory properties of AR-R17779. In peritoneal macrophages, both nicotinic agonists reduced nuclear factor kappaB transcriptional activity and proinflammatory cytokine production, with nicotine being more effective than AR-R17779. CONCLUSIONS:
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Authors | Frans O The, Guy E Boeckxstaens, Susanne A Snoek, Jenna L Cash, Roel Bennink, Gregory J Larosa, Rene M van den Wijngaard, David R Greaves, Wouter J de Jonge |
Journal | Gastroenterology
(Gastroenterology)
Vol. 133
Issue 4
Pg. 1219-28
(Oct 2007)
ISSN: 0016-5085 [Print] United States |
PMID | 17919496
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- AR-R 17779
- Anti-Inflammatory Agents
- Bridged-Ring Compounds
- Chrna7 protein, mouse
- Cytokines
- NF-kappa B
- Nicotinic Agonists
- Receptors, Nicotinic
- Spiro Compounds
- alpha7 Nicotinic Acetylcholine Receptor
- Nicotine
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Topics |
- Animals
- Anti-Inflammatory Agents
(pharmacology, therapeutic use, toxicity)
- Bridged-Ring Compounds
(pharmacology, therapeutic use)
- Cells, Cultured
- Cytokines
(metabolism)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Electric Stimulation Therapy
- Female
- Gastric Emptying
(drug effects)
- Gastroenteritis
(metabolism, physiopathology, prevention & control)
- Ileus
(metabolism, physiopathology, prevention & control)
- Intestines
(drug effects, innervation, physiopathology, surgery)
- Macrophages, Peritoneal
(drug effects, metabolism)
- Mice
- Mice, Inbred BALB C
- NF-kappa B
(metabolism)
- Nicotine
(pharmacology, toxicity)
- Nicotinic Agonists
(pharmacology, therapeutic use, toxicity)
- Postoperative Complications
(metabolism, physiopathology, prevention & control)
- Receptors, Nicotinic
(drug effects, metabolism)
- Spiro Compounds
(pharmacology, therapeutic use)
- Transcription, Genetic
(drug effects)
- Vagotomy
- Vagus Nerve
(surgery)
- alpha7 Nicotinic Acetylcholine Receptor
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