Microsomal Prostaglandin E Synthase-1 Plays a Critical Role in Long-term Motility Dysfunction after Bowel Obstruction

You-Min Lin,Yanbo Tang,Xuan-Zheng Shi,Yu Fu,Shrilakshmi Hegde,Ravi Radhakrishnan

doi:10.1038/s41598-018-27230-6

Abstract

Motility dysfunction is present not only during bowel obstruction (BO), but after obstruction is resolved. Previous studies found that lumen distension associated mechano-transcription of COX-2 and production of PGE2 in gut smooth muscle cells (SMC) account for motility dysfunction during obstruction. We hypothesized that PGE2 may exert autocrine effect in SMC to induce microsomal prostaglandin E synthase-1 (mPGES-1), which contributes to motility dysfunction after obstruction is resolved. Partial colon obstruction was induced in rats with an obstruction band, which was released 7 days later. Rats were further studied in the post-BO state. Circular muscle contractility of the mid colon (previously distended during obstruction) remained suppressed, and colon transit was impaired in the post-BO state. The COX-2, mPGES-1, and PGE2 levels were all increased in the distended bowel during obstruction. However, after obstruction was resolved, COX-2 expression returned to normal, whereas mPGES-1 and PGE2 levels remained increased. Expression of mPGES-1 in colon SMC was inducible by stretch or PGE2. Administration of mPGES-1 inhibitor Cay 10526 either before or after the release of obstruction normalized PGE2 levels and improved motility in the post-BO rats. In conclusion, mPGES-1 plays a critical role in the continuous suppression of motor function in the post-BO state.

Highlights

The current surgical approach for obstruction is to release blockage as in mechanical bowel obstruction (BO), or remove constriction as in HD, but to leave alone the distended oral segment in the gut[6,8]
We found that mechanical stress-induced expression of COX-2 returned to normal level after obstruction is resolved, Microsomal PGE synthase (PGES)-1 (mPGES-1) expression and PGE2 production remained elevated in the post-BO state
We discovered that lumen distention in BO leads to mechano-transcription of COX-2 and other pro-inflammatory mediators in gut smooth muscle[18,31,38,39], and that the mechanical stress-induced COX-2 plays a critical role in the suppression of muscle contractility and motility function during the course of BO18,20,38,39

Summary

Introduction

The current surgical approach for obstruction is to release blockage as in mechanical BO, or remove constriction as in HD, but to leave alone the distended oral segment in the gut[6,8]. Lin et al found that COX-2 inhibitor may have the therapeutic potential in the management of motility dysfunction and associated symptoms during BO20 It remains to be determined whether distention-induced COX-2 and other mechanically sensitive molecules remain up-regulated after obstruction is resolved, and whether expression of these mechanically sensitive genes exert autocrine or paracrine actions to further alter gene expression and gut functions in the previously distended bowel segment. We found that mechanical stress-induced expression of COX-2 returned to normal level after obstruction is resolved, mPGES-1 expression and PGE2 production remained elevated in the post-BO state. We tested the hypotheses that COX-2 –derived PGE2 during obstruction further up-regulates expression of mPGES-1, and that mPGES-1 may play a critical role in the continued production of PGE2 and prolonged motility dysfunction after obstruction is resolved

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