Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice.
OBJECTIVE
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
AR-R17779 treatment potently prevents postoperative ileus, whereas toxicity limits nicotine administration to ineffective doses. Our data further imply that nicotinic inhibition of macrophage activation may involve other receptors in addition to alpha7 nicotinic acetylcholine receptor.
The
Frans O
FO
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.
Boeckxstaens
Guy E
GE
Snoek
Susanne A
SA
Cash
Jenna L
JL
Bennink
Roel
R
Larosa
Gregory J
GJ
van den Wijngaard
Rene M
RM
Greaves
David R
DR
de Jonge
Wouter J
WJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001952:Bridged-Ring Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004599:Electric Stimulation Therapy; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005759:Gastroenteritis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D045823:Ileus / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007422:Intestines / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology / Q000601:surgery; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology / Q000633:toxicity; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011183:Postoperative Complications / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D014628:Vagotomy; D014630:Vagus Nerve / Q000601:surgery; D064569:alpha7 Nicotinic Acetylcholine Receptor
C408128:AR-R 17779; D000893:Anti-Inflammatory Agents; D001952:Bridged-Ring Compounds; C579166:Chrna7 protein, mouse; D016207:Cytokines; D016328:NF-kappa B; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine