Peroxisome proliferator-activated receptor gamma activation alleviates postoperative ileus in mice by inhibition of Egr-1 expression and its downstream target genes.
Postoperative ileus, a major cause of morbidity after abdominal surgery, is characterized by intestinal dysmotility and a complex inflammatory cascade within the intestinal muscularis. Treatment with carbon monoxide (CO)--inhaled or intraperitonea--has been shown to ameliorate bowel dysmotility caused by surgical manipulation of the gut in experimental animals. Recent evidence indicates that CO exerts its anti-inflammatory effects through the induction of peroxisome proliferator-activated receptor (PPAR)-gamma, a nuclear receptor whose activation has been linked to several physiological pathways, including those related to the regulation of intestinal inflammation. The purpose of this study was to evaluate pharmacological activation of PPARgamma in a murine model of postoperative ileus by use of the PPARgamma agonist rosiglitazone. Postoperative bowel dysmotility was induced by surgical manipulation of the colon. The functional severity of postoperative ileus was significantly ameliorated in mice pretreated with rosiglitazone (0.3 to 10 mg/kg i.p.); this was associated with a down-regulation of pro-inflammatory cytokines/chemokines, inducible nitric oxide synthase activity, cyclooxygenase-2 activity, as well as a decrease in leukocyte recruitment into the muscularis of both colon and jejunum. These anti-inflammatory effects were preceded by a PPARgamma-dependent down-regulation of early growth response (Egr)-1, a key regulator of inflammatory gene expression. In conclusion, these results indicate that rosiglitazone significantly attenuates postoperative ileus in mice by suppression of the muscularis inflammatory cascade through a PPARgamma-dependent down-regulation of Egr-1 and encourage the further clinical evaluation of synthetic PPARgamma agonists as pharmacological tool to prevent this postoperative event.
De Backer
Ole
O
Heymans Institute of Pharmacology, Ghent University, B-9000 Ghent, Belgium. Ole.Debacker@UGent.be
Elinck
Ellen
E
Priem
Evelien
E
Leybaert
Luc
L
Lefebvre
Romain A
RA
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003106:Colon / Q000601:surgery; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005769:Gastrointestinal Motility / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D045823:Ileus / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D011183:Postoperative Complications / Q000517:prevention & control*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D051766:Early Growth Response Protein 1; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004247:DNA; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2