COX-2 dependent inflammation increases spinal Fos expression during rodent postoperative ileus.
OBJECTIVE
Cyclooxygenase 2 (COX-2) and prostaglandins (PGs) participate in the pathogenesis of inflammatory postoperative ileus. We sought to determine whether the emerging neuronal modulator COX-2 plays a significant role in primary afferent activation during postoperative ileus using spinal Fos expression as a marker.


METHODS
Rats, and COX-2(+/+) and COX-2(-/-) mice underwent simple intestinal manipulation. The effect of intestinal manipulation on Fos immunoreactivity (IR) in the L(5)-S(1) spinal cord, in situ circumference, and postoperative leucocytic infiltrate of the intestinal muscularis was measured. Postoperative PGE(2) production was measured in peritoneal lavage fluid. The dependence of these parameters on COX-2 was studied in pharmacological (DFU, Merck- Frosst, selective COX-2 inhibitor) and genetic (COX-2(-/-) mice) models.


RESULTS
Postoperative Fos IR increased 3.7-fold in rats and 2.2-fold in mice. Both muscularis leucocytic infiltrate and the circumference of the muscularis increased significantly in rats and COX-2(+/+) mice postoperatively, indicating dilating ileus. Surgical manipulation markedly increased PGE(2) levels in the peritoneal cavity. DFU pretreatment and the genetic absence of COX-2(-/-) prevented dilating ileus, and leucocytic infiltrate was diminished by 40% with DFU and by 54% in COX-2(-/-) mice. DFU reversed postsurgical intra- abdominal PGE(2) levels to normal. Fos IR after intestinal manipulation was attenuated by approximately 50% in DFU treated rats and in COX-2(-/-) mice.


CONCLUSIONS
Postoperatively, small bowel manipulation causes a significant and prolonged increase in spinal Fos expression, suggesting prolonged primary afferent activation. COX-2 plays a key role in this response. This activation of primary afferents may subsequently initiate inhibitory motor reflexes to the gut, contributing to postoperative ileus.
Kreiss
C
C
Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
Birder
L A
LA
Kiss
S
S
VanBibber
M M
MM
Bauer
A J
AJ
D000818:Animals; D001202:Ascitic Fluid / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D007418:Intestinal Pseudo-Obstruction / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D007421:Intestine, Small / Q000473:pathology / Q000601:surgery*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D015854:Up-Regulation
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D004791:Enzyme Inhibitors; D005663:Furans; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone