Mechano‐transcription of COX‐2 is a common response to lumen dilation of the rat gastrointestinal tract

Abstract

Background In obstructive bowel disorders (OBDs) such as achalasia, pyloric stenosis, and bowel obstruction, the lumen of the affected segments is markedly dilated and the motility function is significantly impaired. We tested the hypothesis that mechanical stress in lumen dilation leads to induction of cyclooxygenase‐2 (COX‐2) in smooth muscle throughout the gastrointestinal (GI) tract, contributing to motility dysfunction. Methods Lumen dilation was induced in vivo with obstruction bands (12 × 3 mm) applied over the lower esophageal sphincter (LES), the pyloric sphincter, and the ileum in rats for 48 h. Mechanical stretch in vivo was also emulated by balloon distension of the distal colon. Direct stretch of muscle strips from the esophagus, gastric fundus, and ileum was mimicked in an in vitro tissue culture system. Key Results Partial obstruction in the LES, pylorus, and ileum significantly increased the expression of COX‐2 mRNA and protein in the muscularis externae of the dilated segment oral to the occlusions, but not in the aboral segment. Direct stretch of the lumen in vivo or of muscle strips in vitro markedly induced COX‐2 expression. The smooth muscle contractility was significantly suppressed in the balloon‐distended segments. However, treatment with COX‐2 inhibitor NS‐398 restored the contractility. Furthermore, in vivo administration of NS‐398 in gastric outlet obstruction significantly improved gastric emptying. Conclusions & Inferences Mechanical dilation of the gut lumen by occlusion or direct distension induces gene expression of COX‐2 throughout the GI tract. Mechanical stress‐induced COX‐2 contributes to motility dysfunction in conditions with lumen dilation.

Pathogenesis of abdominal pain in bowel obstruction: role of mechanical stress-induced upregulation of nerve growth factor in gut smooth muscle cells

“…Mechanical stress was found to increase NGF expression in vascular smooth muscle cells (SMC) in vitro [7]. We tested a hypothesis in the present study that lumen distention associated mechanical stress induces gene expression (mechano-transcription) [22, 25, 27, 39, 50] of NGF in colonic SMC, and that mechanical stress-induced NGF from SMC sensitizes afferent neurons and contributes to abdominal pain in OBD. We found that NGF expression in colonic smooth muscle was significantly up-regulated by mechanical stress in distended colon segment in a rat model of bowel obstruction and in the primary culture of rat colonic SMC in vitro .…”

“…The rat model of partial colon obstruction was prepared by following procedures described previously [22, 25, 39]. In brief, rats were anesthetized with 2% isoflurane inhalation by an E-Z Anesthesia vaporizer (Palmer, PA).…”

“…One microgram of total RNA was reverse-transcribed with the SuperScript III First-Strand Synthesis System (Invitrogen) for quantitative RT-PCR with the Applied Biosystems 7000 real-time PCR system (Foster City, CA) [22, 25, 27, 39, 50]. The assay IDs for TaqMan detection of rat NGF, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 mRNAs are Rn01533872_m1, Rn00591020_m1, Rn00570506_m1, Rn00568393_m1, and Rn00570487_m1, respectively (Applied Biosystems).…”

Enhanced cyclooxygenase-2 activity leads to intestinal dysmotility following hemorrhagic shock

“…COX-2 is an inducible form of the enzyme produced in a variety of stress conditions, such as sepsis 4 , tumor 5 , operative manipulation 6 and bowel obstruction 7 . Recent studies indicate that inducible expression of COX-2 in endotoxemia rats induces the motility disturbance of intestine 8,9 .…”

Mechanical Stress Is a Pro-Inflammatory Stimulus in the Gut: In Vitro, In Vivo and Ex Vivo Evidence

“…PGE 2 [25], [26] in gut SMCs. We found that COX-2, through its principal catalytic product PGE 2 , plays a critical role in motility dysfunction in bowel obstruction and other conditions with lumen distention [26], [27]. The so-called phospholipase A 2 /COX-2/prostaglandin E synthase /PGE 2 (PCPP) axis is one of the best-studied pathways implicated in inflammatory regulation [28], [29].…”