EP4 agonist alleviates indomethacin-induced gastric lesionsand promotes chronic gastric ulcer healing

Abstract

EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…Hoshino et al (2003) demonstrated that EP4 activation inhibited ethanol-induced apoptosis in primary culture of guinea pig gastric mucosa cells through the cAMP-PKA pathway, but not the PI3K pathway. Similar results were shown in indomethacin-induced apoptosis in human gastric mucosa cells (Jiang et al, 2009). An antiapoptotic effect of cAMP has also been demonstrated in the T84 intestinal epithelial cell line (Nishihara et al, 2003;Rudolph et al, 2004Rudolph et al, , 2007.…”

“…Mucosal cell injury. Several in vivo studies suggested that EP4 activation plays a protective role in rodent models of gastric ulcer via different mechanisms, such as VEGF induction, venous relaxation, and inhibition of apoptosis (Hatazawa et al, 2007;Hattori et al, 2008;Jiang et al, 2009), although there are reports that EP4 did not contribute to ulcer healing (Kunikata et al, 2001;Takeuchi et al, 2003). Takeuchi et al (2010b) found that an EP4 agonist reversed indomethacin-induced downregulation of VEGF expression and angiogenesis, and suggested that endogenous PGE 2 promotes the healing of small intestinal lesions by stimulating angiogenesis through the upregulation of VEGF expression mediated by the activation of EP4 receptors.…”

Prostaglandin E2Promotes Wound-Induced Migration of Intestinal Subepithelial Myofibroblasts via EP2, EP3, and EP4 Prostanoid Receptor Activation

“…Studies have shown that PGE 2 -EP4 signaling accelerates the repair of gastrointestinal ulcers in a mouse model (Jiang et al, 2009;Takeuchi et al, 2010). Another study has shown that ISMFs strongly express COX-2 in a chronic inflammation model in mice (Davids et al, 2010).…”

Comparison of Prostaglandin E2 Receptor Subtype 4 Agonist and Sulfasalazine in Mouse Colitis Prevention and Treatment

“…EP4 knockout mice are most susceptible to IBD induction (Kabashima et al, 2002). Moreover, agonists for EP4 have been shown to inhibit the production of chemokines and cytotoxic cytokines from immune cells (Yamane et al, 2000;Nitta et al, 2002;Takayama et al, 2002;Ratcliffe et al, 2007), suppress inflammation at lesions of the gastrointestinal tract (Kabashima et al, 2002;Jiang et al, 2009), and promote epithelial cell survival and growth by activating antiapoptotic and proliferative cellular signaling pathways (Fujino et al, 2003;Hoshino et al, 2003;Joseph et al, 2005;Jiang et al, 2007). In live animals, EP4 agonists from several distinct chemical templates have been shown to prevent and improve IBD symptoms (Kabashima et al, 2002;Nitta et al, 2002;Jiang et al, 2007).…”