Title:Roles of Cyclooxygenase, Prostaglandin E2 and EP Receptors in Mucosal Protection and Ulcer Healing in the Gastrointestinal Tract
Volume: 24
Issue: 18
Author(s): Koji Takeuchi*Kikuko Amagase*
Affiliation:
- Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414,Japan
- Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414,Japan
Keywords:
prostaglandin E2, EP receptor subtype, mucosal protection, healing, gastrointestinal tract, cyclooxygenase.
Abstract: Endogenous prostaglandins (PGs), produced from arachidonic acid by the two isoforms of
cyclooxygenase (COX), play a pivotal role in maintaining mucosal integrity by modulating various functions of
the gastrointestinal (GI) tract, and PGE2 is most effective in these actions. The PGE2 receptor is classified into 4
specific G-protein coupled subtypes, EP1-EP4, and their distribution accounts for the multiple effects of this
prostanoid. PGE2 prevents acid-reflux esophagitis and indomethacin-induced gastric lesions through EP1
receptors, while endogenous PGs protect the stomach against cold restraint stress mediated by mainly PGI2/IP
receptors and partly EP4 receptors. PGE2 also exhibits a protective effect against acid-induced duodenal damage
and indomethacin-induced small intestinal lesions mediated by EP3/EP4 receptors; these effects in the stomach,
duodenum, or small intestine are associated functionally with inhibition of gastric contraction (EP1), stimulation
of duodenal HCO3
- secretion (EP3/EP4), or suppression of bacterial invasion due to the inhibition of intestinal
motility (EP4) as well as stimulation of mucus secretion (EP3/EP4), respectively. PGE2 also prevents ischemiainduced
enteritis and dextran sulfate sodium-induced colitis mediated by EP4 receptors, and the protective
mechanisms may be related to the stimulation of mucus secretion and the down-regulation of immune response,
respectively. Furthermore, PGE2 shows a healing-promoting effect on gastric ulcers and small intestinal lesions
through the up-regulated expression of vascular endothelial growth factor (VEGF) and stimulation of
angiogenesis via the activation of EP4 receptors. Finally, COX-1 is mainly responsible for the production of
endogenous PGs involved in mucosal protection, while COX-2 is mainly responsible for those involved in the
healing of gastric ulcers or small intestinal lesions. These findings contribute to future development of new
strategies for the treatment of GI diseases.