EP2 Receptor Blockade Attenuates COX-2 Upregulation during Intestinal Inflammation

Jamie Golden, Laura Illingworth, Patil Kavarian, Oswaldo Escobar, Patrick Delaplain, Mubina Isani, Jin Wang, Joanna Lim, Jordan Bowling, Brandon Bell, Christopher P. Gayer, Anatoly Grishin, Henri Ford

Research output: Contribution to journalArticle

Abstract

High levels of PGE2 have been implicated in the pathogenesis of intestinal inflammatory disorders such as necrotizing enterocolitis (NEC) and peritonitis. However, PGE2 has a paradoxical effect: its low levels promote intestinal homeostasis, whereas high levels may contribute to pathology. These concentration-dependent effects are mediated by four receptors, EP1-EP4. In this study, we evaluate the effect of blockade of the low affinity pro-inflammatory receptors EP1 and EP2 on expression of COX-2, the rate limiting enzyme in PGE2 biosynthesis, and on gut barrier permeability using cultured enterocytes and three different models of intestinal injury. PGE2 upregulated COX-2 in IEC-6 enterocytes, and this response was blocked by the EP2 antagonist PF-04418948, but not by the EP1 antagonist ONO-8711 or EP4 antagonist E7046. In the neonatal rat model of NEC, EP2 antagonist and low dose of COX-2 inhibitor Celecoxib, but not EP1 antagonist, reduced NEC pathology as well as COX-2 mRNA and protein expression. In the adult mouse endotoxemia and cecal ligation/puncture models, EP2, but not EP1 genetic deficiency decreased COX-2 expression in the intestine. Our results indicate that the EP2 receptor plays a critical role in the positive feedback regulation of intestinal COX-2 by its end-product PGE2 during inflammation and may be a novel therapeutic target in the treatment of NEC.

Original languageEnglish (US)
JournalShock
DOIs
StateAccepted/In press - Jan 1 2019

Keywords

  • COX-2
  • EP2 receptor
  • intestinal inflammation
  • mice
  • rats

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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    Golden, J., Illingworth, L., Kavarian, P., Escobar, O., Delaplain, P., Isani, M., Wang, J., Lim, J., Bowling, J., Bell, B., Gayer, C. P., Grishin, A., & Ford, H. (Accepted/In press). EP2 Receptor Blockade Attenuates COX-2 Upregulation during Intestinal Inflammation. Shock. https://doi.org/10.1097/SHK.0000000000001444