Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2

Xuan-Zheng Shi,Sushil K Sarna,Don W Powell,You-Min Lin

doi:10.1152/ajpgi.00379.2010

Abstract

In gastrointestinal conditions such as bowel obstruction, pseudo-obstruction, and idiopathic megacolon, the lumen of affected bowel segments is distended and its motility function impaired. Our hypothesis is that mechanical stretch of the distended segments alters gene expression of cyclooxygenase-2 (COX-2), which impairs motility function. Partial obstruction was induced with a silicon band in the distal colon of rats for up to 7 days, and wild-type and COX-2 gene-deficient mice for 4 days. Mechanical stretch was mimicked in vitro in colonic circular muscle strips and in primary culture of colonic circular smooth muscle cells (SMC) with a Flexercell system. The rat colonic circular muscle contractility was significantly decreased in the distended segment oral to obstruction, but not in the aboral segment. This change started as early as day 1 and persisted for at least 7 days after obstruction. The expression of COX-2 mRNA and protein increased dramatically also in the oral, but not aboral, segment. The upregulation of COX-2 expression started at 12 h and the effect persisted for 7 days. At 24 h after obstruction, the COX-2 mRNA level in the oral segment increased 26-fold compared with controls. This was not accompanied by any significant increase of myeloperoxidase or inflammatory cytokines. Immunohistochemical studies showed that COX-2 was selectively induced in the colonic SMC. In vitro stretch of colonic muscle strips or cultured SMC drastically induced COX-2 expression. Incubation of circular muscle strips from obstructed segment with COX-2 inhibitor NS-398 restored the contractility. The impairment of muscle contractility in obstructed colon was attenuated in the COX-2 gene-deficient mice. In conclusion, mechanical stretch in obstruction induces marked expression of COX-2 in the colonic SMC, and stretch-induced COX-2 plays a critical role in the suppression of smooth muscle contractility in bowel obstruction.

Highlights

BOWEL OBSTRUCTION OCCURS IN the small and large intestines, and may be mechanical or functional [32, 37]
In the muscularis tissue taken 1 day after the laparotomy, we found no significant increase of inflammatory mediators such as intercellular adhesion molecule-1 (ICAM-1), interleukin-1␤ (IL-1␤), or tumor necrosis factor-␣ (TNF-␣) in the oral or aboral segments compared with sham controls (Fig. 2A)
Motility impairment in bowel obstruction is associated with symptoms such as bloating, vomiting, abdominal pain, and constipation, all of which compromise digestive function

Summary

Introduction

BOWEL OBSTRUCTION OCCURS IN the small and large intestines, and may be mechanical or functional [32, 37]. A series of changes occurs in the obstructed segments, including altered motility function, and increased thickness of the muscle layer (hypertrophy) [2, 10, 24, 33, 39] These changes are responsible for symptoms such as bloating, vomiting, abdominal cramps, and constipation [16, 30, 32, 33, 37] and may lead to intestinal failure [33]. Our data demonstrate that colon obstruction leads to a dramatic increase of COX-2 gene expression selectively in the smooth muscle cells (SMCs) of the segment oral to the site of obstruction. Using selective COX-2 inhibitors and COX-2 genedeficient mice, we determined that stretch-induced COX-2 in the colonic SMC plays a critical role in obstruction-associated contractility impairments

Methods

Results

Conclusion