Prophylactic and therapeutic benefits of COX-2 inhibitor on motility dysfunction in bowel obstruction: roles of PGE₂ and EP receptors

Abstract

We reported previously that mechanical stretch in rat colonic obstruction induces cyclooxygenase (COX)-2 expression in smooth muscle cells. The aims of the present study were to investigate whether in vivo treatment with COX-2 inhibitor has prophylactic and therapeutic effects on motility dysfunction in colon obstruction, and if so what are the underlying mechanisms. Partial colon obstruction was induced with a silicon band in the distal colon of 6 -8-wk-old Sprague-Dawley rats; obstruction was maintained for 3 days or 7 days. Daily administration of COX-2 inhibitor NS-398 (5 mg/kg) or vehicle was started before or after the induction of obstruction to study its prophylactic and therapeutic effects, respectively. The smooth muscle contractility was significantly suppressed, and colonic transit rate was slower in colonic obstruction. Prophylactic treatment with NS-398 significantly prevented the impairments of colonic transit and smooth muscle contractility and attenuated fecal collection in the occluded colons. When NS-398 was administered therapeutically 3 days after the initiation of obstruction, the muscle contractility and colonic transit still improved on day 7. Obstruction led to marked increase of COX-2 expression and prostaglandin E 2 (PGE2) synthesis. Exogenous PGE2 decreased colonic smooth muscle contractility. All four PGE2 E-prostanoid receptor types (EP1 to EP4) were detected in rat colonic muscularis externa. Treatments with EP1 and EP3 antagonists suppressed muscle contractility in control tissue but did not improve contractility in obstruction tissue. On the contrary, the EP2 and EP4 antagonists did not affect control tissue but significantly restored muscle contractility in obstruction. We concluded that our study shows that COX-2 inhibitor has prophylactic and therapeutic benefits for motility dysfunction in bowel obstruction. PGE2 and its receptors EP2 and EP4 are involved in the motility dysfunction in obstruction, whereas EP1 and EP3 mediate PGE2 regulation of colonic smooth muscle contractile function in normal state.

Microbiota dysbiosis and its pathophysiological significance in bowel obstruction

“…Consistent with previous findings 1,29,30 , colonic smooth muscle contractile response was dramatically suppressed in OB. However, antibiotic treatment did not improve colon muscle contractility in OB (Fig.…”

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

“…Administration of COX-2 inhibitors in vivo in gastric outlet obstruction prevented impairments of smooth muscle contractility, and improved gastric emptying. Previously, we have demonstrated that COX-2 inhibitor has prophylactic and therapeutic benefits for motility dysfunction in the obstructed colons [9, 32]. …”

“…The segments were cleansed, opened along the mesenteric border, and pinned flat in Krebs buffer in a petri dish with Sylgard base. The mucosa/submucosa (M/S) and muscularis externa (ME) layers were separated by microdissection as described previously, and the ME was taken for the molecular measurements [9, 27-32]. …”

“…One microgram of total RNA was reverse-transcribed using the SuperScript III First-Strand Synthesis System (Invitrogen, Carlsbad, CA) for real-time quantitative PCR with an Applied Biosystems 7000 real-time PCR system (Foster City, CA) [9, 29-32]. The assay ID for Taqman detection of rat COX-2 mRNA is Rn00568225-m1 (Applied Biosystems).…”

“…The contractile activity was recorded as previously described [9, 30-32] with Grass isometric force transducers and amplifiers connected to Biopac data-acquisition system (Biopac Systems, Goleta, CA). The muscle strips were first equilibrated in the muscle bath under 1 g tension for 60 min at 37°C.…”