Open AccessEP2 Receptor Blockade Attenuates COX-2 Upregulation During Intestinal Inflammation
Author(s) -
Jamie Golden,
Laura Illingworth,
Patil Kavarian,
Oswaldo H. Escobar,
Patrick T. Delaplain,
Mubina Isani,
Jin Wang,
Joanna C. Lim,
Jordan D. Bowling,
Brandon Bell,
Christopher P. Gayer,
Anatoly Grishin,
Henri R. Ford
Publication year - 2019
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/shk.0000000000001444
Subject(s) - prostaglandin e2 receptor , downregulation and upregulation , antagonist , receptor , inflammation , blockade , pathogenesis , enterocyte , receptor antagonist , pharmacology , endocrinology , medicine , chemistry , small intestine , biochemistry , gene , agonist
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.