Activation of the Cholinergic Anti-Inflammatory Pathway Ameliorates Postoperative Ileus in Mice

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 133; no. 4; pp. 1219 - 1228
• Main Authors: The, Frans O, Boeckxstaens, Guy E, Snoek, Susanne A, Cash, Jenna L, Bennink, Roel, LaRosa, Gregory J, van den Wijngaard, Rene M, Greaves, David R, de Jonge, Wouter J
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2007
• Subjects: alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Anti-Inflammatory Agents - toxicity; Bridged-Ring Compounds - pharmacology; Bridged-Ring Compounds - therapeutic use; Cells, Cultured; Cytokines - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation Therapy; Female; Gastric Emptying - drug effects; Gastroenteritis - metabolism; Gastroenteritis - physiopathology; Gastroenteritis - prevention & control; Gastroenterology and Hepatology; Ileus - metabolism; Ileus - physiopathology; Ileus - prevention & control; Intestines - drug effects; Intestines - innervation; Intestines - physiopathology; Intestines - surgery; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred BALB C; NF-kappa B - metabolism; Nicotine - pharmacology; Nicotine - toxicity; Nicotinic Agonists - pharmacology; Nicotinic Agonists - therapeutic use; Nicotinic Agonists - toxicity; Postoperative Complications - metabolism; Postoperative Complications - physiopathology; Postoperative Complications - prevention & control; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - metabolism; Spiro Compounds - pharmacology; Spiro Compounds - therapeutic use; Transcription, Genetic - drug effects; Vagotomy; Vagus Nerve - surgery; Keratinocyl-derived chemokins (CXCL1); nuclear factor κB; electrical vagal nerve stimulation; IM; subdiaphragmal bilateral vagotomy; VGX; STAT3; EMS; signal transducer and activator of transcription 3; POI; L; TNF; laparotomy; LPS; NF-κB; tumor necrosis factor; nAChR; nicotinergic acetylcholine receptor; postoperative ileus; KC; intestinal manipulation; lipopolysaccharide
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2007.07.022

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-κB 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: Lsaline 14% ± 4% vs IMsaline 38% ± 10%, P = .04). Pretreatment with AR-R17779 prevented delayed gastric emptying (IMAR-R17779 15% ± 4%, P = .03). IM elicited inflammatory cell recruitment (Lsaline 50 ± 8 vs IMsaline 434 ± 71 cells/mm2 , P = .001) which was reduced by AR-R17779 pretreatment (IMAR-R17779 231 ± 32 cells/mm2 , 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 κB 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.