Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus

doi:10.1053/gast.2001.29605

Gastroenterology

Volume 121, Issue 6, December 2001, Pages 1354-1371

https://doi.org/10.1053/gast.2001.29605 Get rights and content

Abstract

Background & Aims: This study demonstrates a significant role for cyclooxygenase (COX)-2 and prostanoid production as mechanisms for surgically induced postoperative ileus. Methods: Rats, COX-2^+/+, and COX-2^−/− mice underwent simple intestinal manipulation. Reverse-transcription polymerase chain reaction and immunohistochemistry were used to detect and localize COX-2 expression. Prostaglandin levels were measured from serum, peritoneal lavage fluid, and muscularis culture media. Jejunal circular muscle contractions were measured in an organ bath, and gastrointestinal transit was measured in vivo. Results: The data show that intestinal manipulation induces COX-2 messenger RNA and protein within resident muscularis macrophages, a discrete subpopulation of myenteric neurons and recruited monocytes. The manipulation-induced increase in COX-2 expression resulted in significantly elevated prostaglandin levels within the circulation and peritoneal cavity. The source of these prostanoids could be directly attributed to their release from the inflamed muscularis externa. As a consequence of the molecular up-regulation of COX-2, we observed a decrease in in vitro jejunal circular muscle contractility and gastrointestinal transit, both of which could be alleviated pharmacologically with selective COX-2 inhibition. These studies were corroborated with the use of COX-2^−/− mice. Conclusions: Prostaglandins, through the induction of COX-2, are major participants in rodent postoperative ileus induced by intestinal manipulation.

GASTROENTEROLOGY 2001;121:1354-1371

Section snippets

Animals

AxC 9935 Irish, inbred strain male rats (ACI) (200–250 g) were obtained from Harlan-Sprague-Dawley (Indianapolis, IN). Homozygous wild-type (WT) C57BL/6 mice as well as homozygous COX-2^−/− knockout (KO) mice weighing 18–20 grams were kindly provided by Dr. S. H. Graham, Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania. The homozygous COX-2^−/− KO mice resulted from a cross of COX-2^+/− heterozygote C57BL/6 mice (B6,129S-Ptgs2^tm1Jed; Jackson Laboratories, Bar Harbor, ME).

Intestinal manipulation up-regulates the expression of COX-2 mRNA

Intestinal manipulation initiates a complex molecular and cellular inflammatory response within the intestinal muscularis that leads to intestinal ileus, and we have shown that inducible NO plays a major role in this response.17, 51 However, it seems logical that within this complex inflammatory milieu other kinetically active mediators are also involved. Because eicosanoids are such potently active kinetic substances on smooth muscle,59, 60 we designed experiments to determine if intestinal

Discussion

This study for the first time shows a significant role for COX-2 and prostanoid production as a mechanism for surgically induced postoperative ileus. The above data show that intestinal manipulation induces COX-2 mRNA and protein within resident muscularis macrophages, a discrete subpopulation of myenteric neurons and recruited monocytes. This manipulation-induced increase in COX-2 expression resulted in a significant elevation of prostaglandin levels within the circulation and the peritoneal

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^☆: Supported by National Institutes of Health grants R01-GM-58241 and P50-GM-53789 and a grant from the Deutsche Forschungsgemeinschaft Schw 745 1/1 (to N.T.S.).

^☆☆: Address requests for reprints to: Anthony J. Bauer, Ph.D., Department of Medicine/Gastroenterology, S-849 Scaife Hall, 3550 Terrace Street, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15261. e-mail: [email protected]; fax: (412) 648-9731.

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Basic ScienceProstanoid production via COX-2 as a causative mechanism of rodent postoperative ileus☆,☆☆

Abstract

Section snippets

Animals

Intestinal manipulation up-regulates the expression of COX-2 mRNA

Discussion

Lancet

Peptides

Eur J Pharmacol

Gastroenterology

J Surg Res

Surgery

Gastroenterology

Gastroenterology

Gastroenterology

Arch Biochem Biophys

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Cell

Gastroenterology

Cell

Cell

Gastroenterology

Biochem Biophys Acta

Gastroenterology

J Biol Chem

J Biol Chem

J Biol Chem

Anal Biochem

FEBS Lett

Lancet

Gastroenterology

J Surg Res

Postoperative ileus

Dig Dis Sci

Resolution of postoperative ileus in humans

Ann Surg

Postoperative ileus in the rat: physiopathology, etiology and treatment

Ann Surg

Pathophysiology of postoperative ileus

Arch Surg

Role of CRF in stress-related alterations of gastric and colonic motor function

Ann N Y Acad Sci

Effect of adrenergic and nitrergic blockade on experimental ileus in rats

Br J Pharmacol

Gastrointestinal motility studies as a guide to postoperative management

Ann Surg

Role of VIP1/PACAP receptors in postoperative ileus

Br J Pharmacol

Lipopolysaccharide activates the intestinal muscularis macrophage network and suppresses circular smooth muscle activity

Am J Physiol

Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis

J Clin Invest

Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and IL-6 production in vivo

J Exp Med

Co-induction of nitric oxide synthase and cyclo-oxygenase: interactions between nitric oxide and prostanoids

Br J Pharmacol

Basic Science
Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus☆,☆☆