Roles of Cyclooxygenase, Prostaglandin E2 and EP Receptors in Mucosal Protection and Ulcer Healing in the Gastrointestinal Tract

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 PGE(2) is most effective in these actions. The PGE(2) receptor is classified into 4 specific G-protein coupled subtypes, EP1-EP4, and their distribution accounts for the multiple effects of this prostanoid. PGE(2) 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 PGI(2)/IP receptors and partly EP4 receptors. PGE(2) 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. PGE(2) also prevents ischemia-induced 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, PGE(2) 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.