GLP-2 receptor agonism ameliorates inflammation and gastrointestinal stasis in murine postoperative ileus.

Abstract

Glucagon-like peptide 2 (GLP-2) is a pleiotropic intestinotrophic hormone that we hypothesized could lessen gastrointestinal inflammation associated with postoperative ileus (POI). To test this idea, the prophylactic timing and dose of a long-acting variant of human GLP-2 linked to the Fc portion of murine immunoglobulin G (IgG) (GLP-2/IgG) was optimized in a murine model of POI. Surgically treated mice received a single dose of GLP-2/IgG, IgG isotype control, or phosphate-buffered saline 1 to 48 h before small bowel surgical manipulation. The distribution of orally fed fluorescein isothiocyanate-dextran and histological analyses of myeloperoxidase-positive immune cells were determined 24 and 48 h postoperatively. TaqMan quantitative polymerase chain reaction was used to determine early changes in mRNA expression in the muscularis or mucosa. In normal mice, prolonged exposure to GLP-2 increased upper gastrointestinal (GI) transit and mucosal weight. When administered 1 or 3 h before surgery, GLP-2/IgG reduced the leukocyte infiltrate 24 and 48 h postoperatively and improved GI transit 48 h postoperatively. Surgical manipulation rapidly increased gene expression of proinflammatory cytokines and enzymes for kinetically active mediators in the mucosa and muscularis. GLP-2/IgG2a affected the expression of genes associated with mucosal inflammation and barrier function. We conclude that prophylactic treatment with a long-acting GLP-2 agonist ameliorates inflammation and improves intestinal dysmotility associated with surgical manipulation of the bowel. The action of GLP-2 is consistent with a lessening of inflammation, leading to a more rapid recovery.

• Authors: Beverley A Moore, Nancy Peffer, Allison Pirone, Ashlyn Bassiri, Sarah Sague, Jeffrey M Palmer, Dana L Johnson, Tom Nesspor, Connie Kliwinski, Pamela J Hornby
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 333 Issue 2 Pg. 574-83 (May 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20167840 (Publication Type: Journal Article)

Chemical References

• Glucagon-Like Peptide-2 Receptor
• Receptors, Glucagon
• Peroxidase

Topics

• Animals
• Disease Models, Animal
• Female
• Gastrointestinal Motility (drug effects, physiology)
• Gene Expression (drug effects, physiology)
• Glucagon-Like Peptide-2 Receptor
• Ileus (drug therapy, physiopathology)
• Inflammation (drug therapy, physiopathology)
• Intestine, Small (metabolism, physiopathology)
• Intestines (drug effects, physiopathology)
• Male
• Mice
• Peroxidase (physiology)
• Postoperative Complications (drug therapy, physiopathology)
• Receptors, Glucagon (agonists, physiology, therapeutic use)