COX-2 dependent inflammation increases spinal Fos expression during rodent postoperative ileus

Kreiss, C.; Birder, L.A.; Kiss, S.; VanBibber, M.M.; Bauer, A.J.
April 2003
Gut;Apr2003, Vol. 52 Issue 4, p527
Academic Journal
Background and aims: 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[sup +/+] and COX-2[sup -/-] mice underwent simple intestinal manipulation. The effect of intestinal manipulation on Fos immunoreactivity (IR) in the L[sub 5]-S[sub 1] spinal cord, in situ circumference, and postoperative leucocytic infiltrate of the intestinal muscularis was measured. Postoperative PGE[sub 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[sup -/-] 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[sup +/+] mice postoperatively, indicating dilating ileus. Surgical manipulation markedly increased PGE[sub 2] levels in the peritoneal cavity. DFU pretreatment and the genetic absence of COX-2[sup -/-] prevented dilating ileus, and leucocytic infiltrate was diminished by 40% with DFU and by 54% in COX-2[sup -/-] mice. DFU reversed postsurgical intra- abdominal PGE[sub 2] levels to normal. Fos IR after intestinal manipulation was attenuated by approximately 50% in DFU treated rats and in COX-2[sup -/-] 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.


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