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Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice.
Gastroenterology. 2007 Oct; 133(4):1219-28.G

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

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.

Authors+Show Affiliations

Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17919496

Citation

The, Frans O., et al. "Activation of the Cholinergic Anti-inflammatory Pathway Ameliorates Postoperative Ileus in Mice." Gastroenterology, vol. 133, no. 4, 2007, pp. 1219-28.
The FO, Boeckxstaens GE, Snoek SA, et al. Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice. Gastroenterology. 2007;133(4):1219-28.
The, F. O., Boeckxstaens, G. E., Snoek, S. A., Cash, J. L., Bennink, R., Larosa, G. J., van den Wijngaard, R. M., Greaves, D. R., & de Jonge, W. J. (2007). Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice. Gastroenterology, 133(4), 1219-28.
The FO, et al. Activation of the Cholinergic Anti-inflammatory Pathway Ameliorates Postoperative Ileus in Mice. Gastroenterology. 2007;133(4):1219-28. PubMed PMID: 17919496.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice. AU - The,Frans O, AU - Boeckxstaens,Guy E, AU - Snoek,Susanne A, AU - Cash,Jenna L, AU - Bennink,Roel, AU - Larosa,Gregory J, AU - van den Wijngaard,Rene M, AU - Greaves,David R, AU - de Jonge,Wouter J, Y1 - 2007/07/25/ PY - 2006/10/25/received PY - 2007/07/12/accepted PY - 2007/10/9/pubmed PY - 2007/10/27/medline PY - 2007/10/9/entrez SP - 1219 EP - 28 JF - Gastroenterology JO - Gastroenterology VL - 133 IS - 4 N2 - 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: 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. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/17919496/Activation_of_the_cholinergic_anti_inflammatory_pathway_ameliorates_postoperative_ileus_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(07)01402-3 DB - PRIME DP - Unbound Medicine ER -