GLP-2 receptor agonism ameliorates inflammation and gastrointestinal stasis in murine postoperative ileus.
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.
Moore
Beverley A
BA
Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania, USA.
Peffer
Nancy
N
Pirone
Allison
A
Bassiri
Ashlyn
A
Sague
Sarah
S
Palmer
Jeffrey M
JM
Johnson
Dana L
DL
Nesspor
Tom
T
Kliwinski
Connie
C
Hornby
Pamela J
PJ
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D000067758:Glucagon-Like Peptide-2 Receptor; D045823:Ileus / Q000188:drug therapy* / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D007421:Intestine, Small / Q000378:metabolism / Q000503:physiopathology; D007422:Intestines / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D009195:Peroxidase / Q000502:physiology; D011183:Postoperative Complications / Q000188:drug therapy / Q000503:physiopathology; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology / Q000627:therapeutic use
D000067758:Glucagon-Like Peptide-2 Receptor; D018027:Receptors, Glucagon; D009195:Peroxidase